Bone treatment systems and methods

ABSTRACT

Systems and methods for treating vertebral compression fractures are provided. A kit can include at least one body containing a bone cement precursor to be mixed with at least one other bone cement precursor to form a bone cement. The body or a package containing the body can include at least one sensor. In some embodiments the sensor can be a temperature sensor. In some methods, data from the sensor can be used to determine certain parameters related to a treatment interval involving the bone cement.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/728,127, filed Mar. 19, 2010, which claims the benefit of priorityunder 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/210,496filed Mar. 19, 2009. This application is also related to U.S. patentapplication Ser. No. 12/024,969, filed on Feb. 1, 2008; Ser. No.12/395,532, filed on Feb. 27, 2009; and Ser. No. 12/512,505, filed onJul. 30, 2009. The entire contents of all of the above applications arehereby incorporated by reference and should be considered a part of thisspecification.

BACKGROUND OF THE INVENTION

Field of the Invention

Embodiments of the present disclosure relate to bone cements and cementinjection systems, and in some embodiments provide systems and methodsfor on-demand control of bone cement viscosity for treating vertebralcompression fractures and for preventing cement extravasation.

Description of the Related Art

Osteoporotic fractures are prevalent in the elderly, with an annualestimate of 1.5 million fractures in the United States alone. Theseinclude 750,000 vertebral compression fractures (VCFs) and 250,000 hipfractures. The annual cost of osteoporotic fractures in the UnitedStates has been estimated at $13.8 billion. The prevalence of VCFs inwomen age 50 and older has been estimated at 26%. The prevalenceincreases with age, reaching 40% among 80-year-old women. Medicaladvances aimed at slowing or arresting bone loss from aging have notprovided solutions to this problem. Further, the population affectedwill grow steadily as life expectancy increases. Osteoporosis affectsthe entire skeleton but most commonly causes fractures in the spine andhip. Spinal or vertebral fractures also cause other serious sideeffects, with patients suffering from loss of height, deformity andpersistent pain which can significantly impair mobility and quality oflife. Fracture pain usually lasts 4 to 6 weeks, with intense pain at thefracture site. Chronic pain often occurs when one vertebral level isgreatly collapsed or multiple levels are collapsed.

Postmenopausal women are predisposed to fractures, such as in thevertebrae, due to a decrease in bone mineral density that accompaniespostmenopausal osteoporosis. Osteoporosis is a pathologic state thatliterally means “porous bones”. Skeletal bones are made up of a thickcortical shell and a strong inner meshwork, or cancellous bone, ofcollagen, calcium salts, and other minerals. Cancellous bone is similarto a honeycomb, with blood vessels and bone marrow in the spaces.Osteoporosis describes a condition of decreased bone mass that leads tofragile bones which are at an increased risk for fractures. In anosteoporosis bone, the sponge-like cancellous bone has pores or voidsthat increase in dimension making the bone very fragile. In young,healthy bone tissue, bone breakdown occurs continually as the result ofosteoclast activity, but the breakdown is balanced by new bone formationby osteoblasts. In an elderly patient, bone resorption can surpass boneformation thus resulting in deterioration of bone density. Osteoporosisoccurs largely without symptoms until a fracture occurs.

Vertebroplasty and kyphoplasty are recently developed techniques fortreating vertebral compression fractures. Percutaneous vertebroplastywas first reported by a French group in 1987 for the treatment ofpainful hemangiomas. In the 1990's, percutaneous vertebroplasty wasextended to indications including osteoporotic vertebral compressionfractures, traumatic compression fractures, and painful vertebralmetastasis. Vertebroplasty is the percutaneous injection of polymethylmethacrylate (PMMA) into a fractured vertebral body via a trocar andcannula. The targeted vertebrae are identified under fluoroscopy. Aneedle is introduced into the vertebrae body under fluoroscopic control,to allow direct visualization. A bilateral transpedicular (through thepedicle of the vertebrae) approach is typical but the procedure can bedone unilaterally. The bilateral transpedicular approach allows for moreuniform PMMA infill of the vertebra.

In a bilateral approach, approximately 1 to 4 ml of PMMA or more is usedon each side of the vertebra. Since the PMMA needs to be forced into thecancellous bone, the techniques require high pressures and fairly lowviscosity cement. Since the cortical bone of the targeted vertebra mayhave a recent fracture, there is the potential of PMMA leakage. The PMMAcement contains radiopaque materials so that when injected under livefluoroscopy, cement localization and leakage can be observed. Thevisualization of PMMA injection and extravasation are critical to thetechnique, as the physician generally terminates PMMA injection whenleakage is observed. The cement is injected using syringes to allow thephysician manual control of injection pressure.

Balloon kyphoplasty is a modification of percutaneous vertebroplasty.Balloon kyphoplasty involves a preliminary step comprising thepercutaneous placement of an inflatable balloon tamp in the vertebralbody. Inflation of the balloon creates a cavity in the bone prior tocement injection. In balloon kyphoplasty, the PMMA cement can beinjected at a lower pressure into the collapsed vertebra since a cavityexists, as compared to conventional vertebroplasty. More recently, otherforms of kyphoplasty have been developed in which various tools are usedto create a pathway or cavity into which the bone cement is theninjected.

The principal indications for any form of vertebroplasty areosteoporotic vertebral collapse with debilitating pain. Radiography andcomputed tomography must be performed in the days preceding treatment todetermine the extent of vertebral collapse, the presence of epidural orforaminal stenosis caused by bone fragment retropulsion, the presence ofcortical destruction or fracture, and the visibility and degree ofinvolvement of the pedicles.

Leakage of PMMA during vertebroplasty can result in very seriouscomplications including compression of adjacent structures thatnecessitate emergency decompressive surgery. See Groen, R. et al.,“Anatomical and Pathological Considerations in PercutaneousVertebroplasty and Kyphoplasty: A Reappraisal of the Vertebral VenousSystem,” Spine Vol. 29, No. 13, pp 1465-1471, 2004. Leakage orextravasation of PMMA is a critical issue and can be divided intoparavertebral leakage, venous infiltration, epidural leakage andintradiscal leakage. The exothermic reaction of PMMA carries potentialcatastrophic consequences if thermal damage were to extend to the duralsac, cord, and nerve roots. Surgical evacuation of leaked cement in thespinal canal has been reported. It has been found that leakage of PMMAis related to various clinical factors such as the vertebral compressionpattern, and the extent of the cortical fracture, bone mineral density,the interval from injury to operation, the amount of PMMA injected andthe location of the injector tip. In one recent study, close to 50% ofvertebroplasty cases resulted in leakage of PMMA from the vertebralbodies. See Hyun-Woo Do et al., “The Analysis of PolymethylmethacrylateLeakage after Vertebroplasty for Vertebral Body Compression Fractures,”J. of Korean Neurosurg. Soc., Vol. 35, No. 5 (May 2004), pp 478-82,(http://www.jkns.or.kr/htm/abstract.asp?no=0042004086).

Another recent study was directed to the incidence of new VCFs adjacentto the vertebral bodies that were initially treated. Vertebroplastypatients often return with new pain caused by a new vertebral bodyfracture. Leakage of cement into an adjacent disc space duringvertebroplasty increases the risk of a new fracture of adjacentvertebral bodies. See Am. J. Neuroradiol., 2004 February; 25(2):175-80.The study found that 58% of vertebral bodies adjacent to a disc withcement leakage fractured during the follow-up period compared with 12%of vertebral bodies adjacent to a disc without cement leakage.

Another life-threatening complication of vertebroplasty is pulmonaryembolism. See Bernhard, J. et al., “Asymptomatic Diffuse PulmonaryEmbolism Caused by Acrylic Cement: An Unusual Complication ofPercutaneous Vertebroplasty,” Ann. Rheum. Dis., 62:85-86, 2003. Thevapors from PMMA preparation and injection also are cause for concern.See Kirby, B, et al., “Acute Bronchospasm Due to Exposure toPolymethylmethacrylate Vapors During Percutaneous Vertebroplasty,” Am.J. Roentgenol., 180:543-544, 2003.

SUMMARY OF THE INVENTION

There is a general need to provide bone cements and methods for use intreatment of vertebral compression fractures that provide a greaterdegree of control over introduction of cement and that provide betteroutcomes. The present disclosure meets this need and provides severalother advantages in a novel and nonobvious manner.

In some embodiments, a system for providing a bone cement for injectioninto a patient, can comprise a bone cement kit and a data transmitter.The bone cement kit can include one or more packages of bone cementprecursors, wherein the bone cement precursors are configured to combineto form a bone cement. The data transmitter can be carried by at leastone of the one or more packages and can be configured to communicateoutput data. In some embodiments, the system can further include a datareceiver. The data receiver can be configured to receive the output datafrom the data transmitter and for providing a signal to one or both ofan electronic controller and system operator.

In some embodiments, the signal indicates at least one of a cementtemperature and a post-mixing start time for injecting the cement. Insome embodiments, the output data can comprise at least one ID parameterselected from the group of monomer or polymer type, volume of monomer orpolymer, and manufacturing lot of the monomer of polymer. In someembodiments, the output data can comprises at least one of a temperatureof a monomer or polymer, and a temperature log of a monomer or polymer.

Certain embodiments can comprise a system for providing a bone cementfor injection into a patient. The system can include a bone cement kitand a data receiver. The bone cement kit of some embodiments cancomprise one or more packages of bone cement components, wherein thebone cement components are configured to combine to form a bone cementand include a liquid monomer component and a powder component. The datareceiver can be configured to receive output data concerning the bonecement components from a data transmitter and for providing a signal toone or both of an electronic controller and system operator.

In some embodiments, the signal can indicate at least one of a cementtemperature and a post-mixing start time for injecting the cement. Insome embodiments, the system can further include the data transmitterwhich can be connected to one of the one or more packages.

A system for providing a bone cement for injection into a patientaccording to some embodiments can comprise a bone cement kit and atleast one temperature sensor. The bone cement kit can comprise one ormore packages of bone cement components, wherein the bone cementcomponents are configured to combine to form a bone cement and include aliquid monomer component and a powder component. The at least onetemperature sensor can be affixed to at least one package of the bonecement components. In some embodiments, the sensor can be configured toindicate the temperature of said bone cement component.

In some embodiments, the one or more packages can comprise at least oneof a vial, ampule, tube, syringe, shipping carton, box, bag, sterilepouch, sterile sac and blister pack. In some embodiments, thetemperature sensor can comprise a temperature strip, and/or athermochromic ink. In some embodiments, the temperature sensor can beaffixed to the package of liquid monomer component.

Embodiments of a method for providing operational information concerninga bone cement, can include various steps. A method can include providinga bone cement kit. The bone cement kit can include one or more packagesof bone cement precursors, wherein the bone cement precursors combine toform a bone cement. In some embodiments, at least one of the one or morepackages can have a radio frequency tag affixed thereto. A method caninclude receiving a signal from a radio frequency tag indicating data ofone or more bone cement precursors. A method can include mixing bonecement precursors to form bone cement. A method can further includedetermining an operational step for the use of the bone cement based onthe data.

In some embodiments, receiving the signal from the radio frequency tagcan be in response to an interrogation signal communicated from acontroller to the one or more packages. In some embodiments, the datacan be at least one of temperature and temperature history. In someembodiments, the operational step can be wait time post-mixing.

A method for providing operational information concerning a bone cementaccording to some embodiments can comprise providing a bone cement kitcomprising at least two packages of bone cement precursors and mixingthe bone cement precursors to provide a bone cement. In someembodiments, the bone cement kit can further include at least onetemperature sensor affixed to one of the packages of bone cementprecursors. The method can also include the step of determining a bonecement injection start time based on temperature from the at least onetemperature sensor.

In some embodiments, the determining step can be derived from a chartand/or provided by an algorithm and computer controller.

According to some embodiments, a method is provide for determining aworking condition of a curable bone cement. The method can comprise oneor more of the following steps: determining a pre-mix temperature of atleast one of first and second bone cement precursors; determining anambient temperature; mixing the first and second bone cement precursorsto form a bone cement; and determining a bone cement injection starttime based at least in part on an algorithm relating to said pre-mix andambient temperatures.

In some embodiment the method can further include one or more of thefollowing steps: actuating a controller and energy source to applyenergy through an emitter to thereby apply heat to the bone cementpost-mixing; actuating the controller to modulate applied energy basedon the pre-mix and ambient temperatures and/or the calculated injectionstart time; and actuating the controller to modulate hydraulic pressurebased on the pre-mix and ambient temperatures and/or the calculatedinjection start time.

In some embodiments, the determining steps can be accomplished at leastby a temperature sensor affixed to containers and/or packaging of thefirst and second bone cement precursors. In some embodiments,determining the pre-mix temperature can comprise determining a pre-mixtemperature history of at least one of first and second bone cementprecursors.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the embodiments of the present disclosureand to see how it may be carried out in practice, some preferredembodiments are next described, by way of non-limiting examples only,with reference to the accompanying drawings, in which like referencecharacters denote corresponding features consistently throughout similarembodiments in the attached drawings.

FIG. 1 is a schematic, perspective view of a bone cement injectionsystem in accordance with one embodiment.

FIG. 2 is a schematic, exploded side view of the system of FIG. 1illustrating some of the bone cement injection components de-mated fromone another.

FIG. 3 is a schematic illustration of one embodiment of a thermalemitter component of the system of FIGS. 1 and 2.

FIG. 4 is a schematic, exploded perspective view components of thesystem of FIGS. 1-2 in combination with an embodiment of a forceapplication and amplification system, a pressurization mechanism and incommunication with an energy source and a controller.

FIG. 5 is an enlarged, assembly view of an embodiment of a forceapplication and amplification system and a pressurization mechanism ofthe system of FIG. 4.

FIG. 6 is a perspective view of some of the components of the system ofFIGS. 1-5 with a perspective view of an embodiment of an energy sourceand controller.

FIG. 7 is chart indicating certain time-viscosity curves for PMMA bonecements.

FIG. 8A is diagram indicating a method of utilizing applied energy andan energy-delivery algorithm to accelerate the polymerization of a PMMAbone cement to provide a selected time-viscosity curve.

FIG. 8B is a chart indicating a modified time-viscosity curve for a PMMAbone cement of FIG. 7 when modified by applied energy from a thermalenergy emitter and a selected energy-delivery algorithm according to anembodiment of the present disclosure.

FIGS. 8C and 8D are images of PMMA bone cement exiting an injector. FIG.8C is PMMA bone cement exiting the injector without applied energy andFIG. 8D is the same PMMA bone cement exiting an injector as modified byapplied energy according to one embodiment of energy-delivery algorithm.

FIG. 9 is chart indicating another modified time-viscosity curve for thePMMA bone cement of FIGS. 7 and 8A when modified by applied energy usingan alternative energy-delivery algorithm.

FIG. 10 is a chart indicating time-viscosity curves for an embodiment ofPMMA bone cement as in FIG. 8A at different ambient temperatures.

FIG. 11 is a view of another embodiment of a bone cement injectionsystem with some components de-mated from one another wherein the systemincludes first and second thermal energy emitters.

FIG. 12 is a plot illustrating setting time as a function of theconcentration of BPO and DMPT present within embodiments of a bonecement composition.

FIG. 13 is a plot illustrating the temperature-time behavior ofembodiments of a bone cement composition under conditions where thecomposition is and is not heated.

FIG. 14 is a plot illustrating the viscosity-time behavior ofembodiments of a bone cement composition heated to temperatures rangingbetween about 25° C. to 55° C.

FIG. 15 is a chart indicating time-viscosity curves for two embodimentsof PMMA bone cement of this disclosure as well as other commerciallyavailable PMMA bone cements.

FIG. 16 is a schematic view of polymer beads of an embodiment of bonecement.

FIG. 17 is a schematic view of polymer beads of another bone cementembodiment.

FIG. 18 is a schematic view of polymer beads of a further embodiment ofbone cement.

FIG. 19 show is a schematic view of polymer beads of an additional bonecement embodiment.

FIG. 20 is a schematic view of polymer beads of another bone cementembodiment.

FIG. 21 is a chart indicating free indicator (BPO) available to beexposed to monomer over a post-mixing interval of a cement.

FIG. 22 is another chart indicating free initiator (BPO) available to beexposed to monomer over a post-mixing interval of a cement.

FIG. 23 is a chart indicating initiator (BPO) availability over apost-mixing interval of another cement.

FIG. 24 is a schematic view of polymer beads of another bone cementembodiment.

FIG. 25 is a chart indicating a time viscosity curve of cement shown inFIG. 23 over a post-mixing interval.

FIG. 26 is a diagram showing certain time intervals for an bone cementin use.

FIG. 27 shows a temperature sensor affixed to a vial containing a bonecement precursor.

FIG. 28 illustrates a temperature sensor affixed to packaging of a bonecement precursor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

For purposes of understanding the principles of the embodiments of thepresent disclosure, reference will now be made to the embodimentsillustrated in the drawings and accompanying text. As background, avertebroplasty procedure using embodiments of the present disclosure mayintroduce the injector of FIGS. 1-2 through a pedicle of a vertebra, orin a parapedicular approach, for accessing the osteoporotic cancellousbone. The initial aspects of the procedure can be similar topercutaneous vertebroplasty wherein the patient is placed in a proneposition on an operating table. The patient is typically under conscioussedation, although general anesthesia is an alternative. The physicianinjects a local anesthetic (e.g., about 1% Lidocaine) into the regionoverlying the targeted pedicle or pedicles, as well as the periosteum ofthe pedicle(s). Thereafter, the physician may use a scalpel to make anapproximately 1 to 5 mm skin incision over each targeted pedicle.Thereafter, a bone cement injector can be advanced through the pedicleinto the anterior region of the vertebral body, which typically is theregion of greatest compression and fracture. The physician confirms theintroducer path posterior to the pedicle, through the pedicle and withinthe vertebral body, by anteroposterior and lateral X-Ray projectionfluoroscopic views or by other methods. The introduction of infillmaterial as described below can be imaged several times, orcontinuously, during the treatment depending on the imaging method.

The terms “bone cement,” “bone fill,” “bone fill material,” “infillmaterial,” and “infill composition” include their ordinary meaning asknown to those skilled in the art and may include any material forinfilling a bone that includes an in-situ hardenable or settable cementand compositions that can be infused with such a hardenable cement. Thefill material also can include other fillers, such as filaments,microspheres, powders, granular elements, flakes, chips, tubules and thelike, autograft or allograft materials, as well as other chemicals,pharmacological agents, or other bioactive agents.

The term “flowable material” includes its ordinary meaning as known tothose skilled in the art and may include a material continuum that isunable to withstand any static shear stress and responds with asubstantially irrecoverable flow (e.g., a fluid), unlike an elasticmaterial or elastomer that responds to shear stress with a recoverabledeformation. Flowable materials may include fill material or compositesthat may include a first, fluid component alone or in combination with asecond, elastic, or inelastic material component that responds to stresswith a flow, no matter the proportions of the first and secondcomponent. It may be understood that the above shear test does not applyto the second component alone.

The term “vertebroplasty” includes its ordinary meaning as known tothose skilled in the art and may include any procedure where fillmaterial is delivered into the interior of a vertebra.

The term “osteoplasty” includes its ordinary meaning as known to thoseskilled in the art and may include any procedure where a fill materialis delivered into the interior of a bone.

In FIG. 1, an embodiment of a system 10 is shown that includes a firstcomponent or bone cement injector 100 which may extend into cancellousbone of a vertebra, and a second component or cement activationcomponent 105 which includes an emitter 110 for applying energy to bonecement. The first and second components 100 and 105 may include a flowpassageway or channel 112 extending therethrough for delivering flowablebone cement into a bone. The bone cement injector component 100 and thecement activation component 105 can be integrated into a unitary deviceor can be de-mateable, as shown in FIG. 2, by a mechanism such as athreaded portion 113 and a rotatable screw-on fitting 114. Otherconfigurations are also possible. As can be seen in FIGS. 1 and 2, asource of bone cement in the form of a syringe-type body 115 can alsocouple to the system, for example, by way of a threaded fitting 116.

Referring to FIG. 2, the bone cement injector 100 may include a proximalend 118 and a distal end 120 with at least one flow outlet 122 thereinto direct a flow of cement into a bone. The extension portion 124 of theinjector 100 can be made of any suitable metal or plastic sleeve withflow channel 112 extending therethrough to the flow outlet 122. The flowoutlet 122 may be present as a side port to direct cement flowtransverse relative to the axis 125 of extension portion 124 or,alternatively, can be positioned at the distal termination of extensionportion 124 in order to direct cement flows distally. In anotherembodiment (not shown) the extension portion 124 can include first andsecond concentric sleeves that can be positioned so as to be rotatedrelative to one another to align or misalign respective first and secondflow outlets to allow selectively directed cement flows to be more orless axial relative to axis 125 of extension portion 124.

Now turning to the cut-away view of FIG. 2, it can be seen that secondcomponent 105 includes a handle portion that carries an emitter 110 forapplying thermal energy to a cement flow within the flow channel 112that extends through the emitter 110. As will be described furtherbelow, the emitter 110 may apply thermal energy to bone cement 130delivered from chamber 132 of source 115 to flow through the emitter 110to therein cause the viscosity of the cement to increase to a selected,higher viscosity value as the cement exits the injector flow outlet 122into bone. The controlled application of energy to bone cement 130 mayenable the physician to select a setting rate for the cement to reach aselected polymerization endpoint as the cement is being introduced intothe vertebra, for example, allowing a high viscosity that will preventunwanted cement extravasation.

Referring to FIGS. 2 and 3, in one embodiment, the thermal energyemitter 110 may be coupled to an electrical source 140 and controller145 by an electrical connector 146 and a cable 148. In FIG. 2, it can beseen that electrical leads 149 a and 149 b may be coupled with connector146 and extend to the emitter 110. As can be seen in FIG. 3, oneembodiment of thermal energy emitter 110 has a wall portion 150 thatincludes a polymeric positive temperature coefficient of resistance(PTCR) material with spaced apart interlaced surface electrodes 155A and155B as described in Provisional Application No. 60/907,469 filed Apr.3, 2007 titled Bone Treatment Systems and Methods. In this embodiment,the thermal emitter 110 and wall 150 thereof may resistively heat tothereby cause controlled thermal effects in bone cement 130 flowingtherethrough. It may be appreciated that FIG. 3 is a schematicrepresentation of one embodiment of thermal energy emitter 110 which canhave any elongated or truncated shape or geometry, tapered ornon-tapered form, or include the wall of a collapsible thin-wallelement. Further, the positive (+) and negative (−) polarity electrodes155A and 155B can have any spaced apart arrangement, for exampleradially spaced apart, helically spaced apart, axially spaced apart orany combination thereof. This resistively heated PTCR material of theemitter 110 may further generate a signal that indicates flow rate asdescribed in Provisional Application No. 60/907,469 which in turn can beutilized by controller 145 to modulate energy applied to the bone cementtherein, and/or modulate the flow rate of cement 130, which can bedriven by a motor or stored energy mechanism. In another embodiment, theemitter can be any non-PTCR resistive heater such as a resistive coilheater.

In other embodiments, the thermal energy emitter 110 can include a PTCRconstant temperature heater as described above or may include one ormore of a resistive heater, a fiber optic emitter, a light channel, anultrasound transducer, an electrode and an antenna. Accordingly in anysuch embodiment, the energy source 140 can include at least one of avoltage source, a radiofrequency source, an electromagnetic energysource, a non-coherent light source, a laser source, an LED source, amicrowave source, a magnetic source and an ultrasound source that isoperatively coupled to the emitter 110.

Referring FIG. 2, it can be understood that a pressure mechanism 190 iscoupleable to a bone cement source or a syringe 115 for driving the bonecement 130 through the system 10. The pressure mechanism 190 can includeany suitable manual drive system or an automated drive system such asany pump, screw drive, pneumatic drive, hydraulic drive, cable drive orthe like. Such automated drive systems may be coupled to controller 145to modulate the flow rate of cement through the system.

In one embodiment, shown in FIGS. 4-6, the system 10 may further includea hydraulic system 162 with a fitting 163 that may detachably couple tofitting 164 of the bone cement source 115. In this embodiment, the bonecement source 115 may include a syringe body with cement-carrying boreor chamber 132 that carries a pre-polymerized, partially polymerized orrecently-mixed bone cement 130 therein. The hydraulic system 162 mayfurther include a rigid plunger or actuator member 175 with o-ring orrubber head 176 that may move in chamber 132 so as to push the cement130 through the syringe chamber 132 and the flow channel 112 in thesystem 100.

Still referring to FIGS. 4-6, a force application and amplificationcomponent 180 of the hydraulic system 162 may be reversibly couple tothe bone cement source 115, where the force application andamplification component 180 includes a body 182 with pressurizable boreor chamber 185 therein that slidably receives the proximal end 186 of anactuator member 175. The proximal end 186 of actuator member 175 mayinclude an o-ring or gasket 187 so that the bore 185 can be pressurizedwith flow media 188 by the pressure source 190 in order to drive theactuator member 175 distally to thereby displace bone cement 130 fromthe chamber 132 in the cement source or syringe 115. In one embodiment,illustrated in FIG. 5, the surface area of an interface 200 between theactuator member 175 and pressurized flow media 188 may be larger thanthe surface area of an interface 200′ between the actuator member 175and the bone cement 130 so as to thereby provide pressure amplificationbetween the pressurizable chamber 185 and chamber 132 of the cementsource or syringe. In one embodiment, as indicated in FIGS. 4 and 5, thesurface area of interface 200 may be at least about 150% of the surfacearea of interface 200′, at least about 200% of the surface area ofinterface 200′, at least about 250% of the surface area of interface200′ and at least about 300% of the surface area of interface 200′.

Referring to FIGS. 4 and 5, in one embodiment, a force application andamplification component 188 may be employed in the following manner. Ina first operation, a bone fill material injector with a displaceable,non-fluid actuator component intermediate a first fluid chamber and asecond cement or fill-carrying chamber may be provided. In a secondoperation, a flow of media may be provided into the first fluid chamberat a first pressure to thereby displace the actuator component toimpinge on and eject bone cement or fill at a higher second pressurefrom the second chamber into a vertebra. In a non-limiting example, asecond pressure may be provided in the cement-carrying chamber 132 thatis greater than the first pressure in the pressurizable chamber 185.

In one embodiment, the second pressure may be at least about 50% higherthan the first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 75% higher thanthe first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 100% higher thanthe first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 200% higher thanthe first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 300% higher thanthe first pressure in the pressurizable chamber 185.

Referring to FIGS. 5 and 6, one embodiment of pressurizing mechanism forproviding pressure to the force application and amplification component180 may include a pneumatic or hydraulic line 205 that extends topressure mechanism 190, such as a syringe pump 210, which is manuallydriven or motor-driven as is known in the art. In one embodiment, asshown in FIG. 6, the syringe pump 210 may be driven by an electric motor211 operatively coupled to controller 145 to allow modulation of thepressure or driving force in combination with the control of energydelivery by emitter 110 from energy source 140.

It may be appreciated that the pressurizing mechanism or pressure source210 can include any type of mechanism or pump known in the art toactuate the actuator member 175 to move the bone cement in chamber 132.For example, a suitable mechanism can include a piezoelectric elementfor pumping fluid, an ultrasonic pump element, a compressed air systemfor creating pressure, a compressed gas cartridge for creating pressure,an electromagnetic pump for creating pressure, an air-hammer system forcreating pressure, a mechanism for capturing forces from a phase changein a fluid media, a spring mechanism that may releasably store energy, aspring mechanism and a ratchet, a fluid flow system and a valve, a screwpump, a peristaltic pump, a diaphragm pump, rotodynamic pumps, positivedisplacement pumps, and combinations thereof.

Referring to FIG. 6, another feature of embodiments of the presentdisclosure is a remote switch 212 for actuating the pressure mechanism190. In one embodiment, a cable 214 extends from the controller 145 sothat the physician can stand outside of the radiation field created byany imaging system used while treating a vertebra or other bonetreatment site. In another embodiment, the switch 212 can be wirelesslyconnected to the system as is known in the art. In another embodiment(not shown), an elongated cable 214 and switch 212 can be directlycoupled to the injector 100 or other component of the system 10.

Now turning to FIGS. 7, 8A and 8B, the figures illustrate certainembodiments of a method wherein controlled application of energy to abone cement 130 can provide a bone cement with a controlled, on-demandincreased viscosity and a controlled set time compared to a prior artbone cement. FIG. 7 depicts a prior art bone cement known in the art,such as a PMMA bone cement, that has a time-viscosity curve 240 wherethe cement substantially hardens or cures within about 8 to 10 minutespost-mixing. On the horizontal axis of FIGS. 7, and 8B, the time pointzero indicates the time at which the mixing of bone cement precursors,such as monomer and polymer components, is approximately completed.

As can be seen in time-viscosity curve 240 for the prior art bonecement, the cement increases in viscosity from about 500 Pa·s to about750 Pa·s from time zero to about 6 minutes post-mixing. Thereafter, theviscosity of the prior art bone cement increases very rapidly over thetime interval from about 6 minutes to 8 minutes post-mixing to aviscosity greater than 4000 Pa·s. A prior art bone cement having thetime-viscosity curve 240 in FIG. 7 may be considered to have a fairlyhigh viscosity for injection in the range of about 500 Pa·s. At thisviscosity range, however, the bone cement can still have flowcharacteristics that result in extravasation.

Still referring to FIG. 7, it can be understood that the curing reactionof the bone cement involves an exothermic chemical reaction thatinitiates a polymerization process that is dictated, at least in part,by the composition of the bone cement precursors, such as one or more ofa PMMA polymer, monomer, and initiator. FIG. 7 indicates at 230 theexothermic curing reaction over time as a gradation, where, the lightergradation region indicates a lesser degree of chemical reaction and heatand the darker gradation region indicates a greater degree of chemicalreaction and heat leading to more rapid polymerization of the bonecement precursors.

Now turning to FIG. 8A, the block diagram illustrates an embodiment of amethod of utilizing applied energy and an energy-delivery algorithm toaccelerate the polymerization of a PMMA bone cement to provide aselected time-viscosity curve as shown in FIG. 8B. In FIGS. 7 and 8B, itcan be seen that the time-viscosity curve 250 of one embodiment of abone cement can have an initial viscosity is in the range of about 750Pa·s at about time zero post-mixing and thereafter the viscosityincreases in a more linear manner over about 10 to 14 minutespost-mixing than the prior art bone cements depicted with curve 240.This embodiment of bone cement that can provide a time-viscosity curve250 as in FIGS. 7 and 8B, may include a PMMA cement composition asdescribed in U.S. Provisional Application No. 60/899,487 filed on Feb.5, 2007, titled Bone Treatment Systems and Methods, and U.S. applicationSer. No. 12/024,969, filed on Feb. 5, 2008, titled Bone TreatmentSystems and Methods, which are each incorporated herein by thisreference in their entirety. As can be seen in FIG. 8B, the bone cement130, or more particularly, the mixing of the cement precursors includesa first curing reaction source for curing the bone cement as describedabove and can result in the predetermined exothermic curing reactionpost-mixing that is indicated by the gradations of reaction under thetime-viscosity curve 250.

Still referring to FIG. 8B, the chart illustrates a PMMA bone cementwith time-viscosity curve 250 together with a modified time-viscositycurve 260. The modified time-viscosity curve may be provided by theapplication of energy employing an embodiment of the system 10 of thepresent disclosure, as depicted in FIGS. 1 and 4-6. In other words, FIG.8B illustrates one embodiment of the present disclosure, where the bonecement 130 undergoes a curing process (i.e., the time-viscosity curve250) owing to self-heating of the composition as components of the bonecement composition react with each other. This curing process may befurther influenced by the applied energy from energy source 140,controller 145 and emitter 110 to provide the modified time-viscositycurve 260 for cement injection into a bone in order to preventextravasation.

As can be understood from FIG. 8B, the modulation of applied energy overtime from the second curing source or emitter 110, indicatedschematically at energy applications Q, Q′, and Q″, can be provided tocomplement the thermal energy generated by the exothermic reaction ofthe bone cement components in order to provide a substantially constantcement viscosity over a selected working time. This aspect ofembodiments of the present disclosure allows, for the first time, theprovision of bone cements having a controlled, and substantiallyconstant, viscosity that is selected so as to inhibit extravasation.

The bone cement 130 and system 10 of embodiments of the presentdisclosure are therefore notable in that a typical treatment of avertebral compression fracture (VCF) requires cement injection over aperiod of several minutes, for example from about 2 to 10 minutes orabout 2 to 6 minutes, or about 2 to 4 minutes. The physician typicallyinjects a small amount of bone cement, for example, about 1 to 2 cc,then pauses cement injection for the purpose of imaging the injectedcement to check for extravasation, then injects additional cement andthen images, etc. The steps of injecting and imaging may be repeatedfrom about 2 to 10 times or more, wherein the complete treatmentinterval can take about 4 to 6 minutes or more. It can be easilyunderstood that a cement with a working time of at least about 5-6minutes is needed for a typical treatment of a VCF, otherwise the firstbatch of cement may be too advanced in the curing process (see curve 240in FIG. 7) and a second batch of cement may need to be mixed. Inembodiments of the cement 130 and system 10 of the present disclosure,however, as indicated in FIG. 8B at 260, the cement viscosity can beapproximately constant, thus providing a very long working time of about8-10 minutes or more.

It should be appreciated that, in the chart of FIG. 8B, the contributionto bone cement curing owing to self-heating of the bone cementcomposition and applied energy are indicated by shaded areas belowcurves 250 and 260. This graphic representation, however, is forconceptual purposes only, as the vertical axis measures viscosity inPa·s. The actual applied energy, indicated at Q to Q″, may be determinedby analysis of the actual polymerization reaction time of a selectedbone cement composition at a selected ambient temperature andatmospheric pressure.

Thus, in one embodiment of the present disclosure, the bone cementsystem includes: a first energy source and a second energy source,different from one another, that facilitate a curing reaction occurringwithin a bone cement. The first energy source includes heat generated byan exothermic curing reaction resulting from mixture of bone cementprecursor components. The second energy source includes thermal energyintroduced into the bone cement by a thermal energy emitter 110 that mayprovide a selected amount of energy to the bone cement. The systemfurther includes a controller 145 that may modulate the thermal energyprovided to the bone cement composition by the thermal energy emitter110. In this manner, the curing reaction of the bone cement compositionmay be controlled over a selected working time. It can be understoodfrom U.S. Provisional Application No. 60/899,487 and U.S. applicationSer. No. 12/024,969, that PMMA cement compositions can be created toprovide highly-extended working times.

The benefits of such viscosity control may be observed in FIGS. 8C and8D, which, respectively, are images of a PMMA bone cement exiting aninjector without applied energy and the same PMMA bone cement exiting aninjector as modified by applied energy according to one embodiment ofenergy-delivery algorithm. The bone cement emerging from the injectorwithout the benefit of applied energy is of relatively low viscosity, asevidenced by the ease with which the bone cement is deformed by theforce of gravity. Such behavior indicates the bone cement of FIG. 8C maybe prone to extravasation. In contrast, the bone cement modified byapplied energy of high viscosity, as evidenced by its accumulation aboutthe end of the injector. Such behavior indicates that the bone cement ofFIG. 8D is not prone to extravasation.

In another embodiment, referring to FIG. 9, the controller 145 may alsoallow the physician to select an energy-delivery algorithm in thecontroller 145 to provide a variable viscosity. For example, analgorithm could provide increases and decreases in cement viscosity asthe cement exits the injector following the application of energy to thecement flow. Beneficially, such algorithms may provide substantiallyautomated control of the application of energy to the composition by thesystem 10.

In another embodiment, a bone treatment system 10 may be provided thatemploys algorithms for modulating energy applied to the bone cementsystem 130. The bone treatment system 130 may include a bone cementinjector system, a thermal energy emitter 110 that may deliver energy tobone cement flowing through the injector system, and a controller. Thecontroller 145 may include hardware and/or software for implementing oneor more algorithms for modulating applied energy from the emitter 110 tobone cement flow. The energy-delivery algorithms may be further employedto increase the applied energy from about zero to a selected value at arate that inhibits vaporization of at least a portion of a monomerportion of the bone cement 130.

In another embodiment, a controller 145 can enable a physician to selecta bone cement viscosity using a selector mechanism operatively connectedto the controller 145. In certain embodiments, the selector mechanismcan initiate one or more of the energy-delivery algorithms. In someembodiments, the physician can select among a plurality of substantiallyconstant viscosities that can be delivered over a working time. Examplesof ranges of such viscosities may include less than about 1,000 Pa·s andgreater than about 1,500 Pa·s. It should be appreciated that, in certainembodiments, from two to six or more such selections can be enabled bythe controller 145, with each selection being a viscosity range usefulfor a particular purpose, such as about 1,000 Pa·s for treating moredense bone when extravasation is of a lesser concern, or between about4,000 Pa·s and 6,000 Pa·s for treatment of a vertebral fracture toprevent extravasation and to apply forces to vertebral endplates toreduce the fracture.

In order to facilitate energy application to the bone cement compositionin a repeatable manner, the system 10 may further include a temperaturesensor 272 disposed in a mixing device or assembly 275 (see FIG. 6). Themixing assembly 275 may include any container that receives bone cementprecursors for mixing before placement of the mixed cement in the bonecement source 115. In certain embodiments, the temperature sensor 272may be placed in the cement mixing assembly 275 because cement may bestored in a hospital in an environment having a lower or highertemperature than the operating room, which may affect the time-viscositycurve of the cement. The temperature sensor 272 can be operativelycoupled to the controller 145 by a cable or a wireless transmittersystem. In certain embodiments, the sensor 272 may be unitary with themixing assembly 275 and disposable. In alternative embodiments, thesensor 272 can be reusable and detachable from the mixing assembly 275.

In another embodiment, still referring to FIG. 6, a temperature sensor276 may be operatively connected to one or more packages 280 of the bonecement precursors to thereby indicate the actual temperature of thecement precursor(s) prior to mixing. Such a temperature sensor 276 mayindicate the stored temperature and/or the length of time that suchcement precursors have been in the operating room when compared toambient room temperature measured by sensor 270 in the controller 145.This sensor 276 can include one or more temperature sensors that mayinclude, but are not limited to, thermocouples, or thermochromic inks.The temperature sensors 276 may be further disposed on the surface ofthe bone cement package 280, allowing for visual identification of thetemperature of the cement precursors. In this manner, a doctor ortechnician may read the temperature of the package 280 and manuallyinput this temperature into the controller 145 to enable automaticadjustment of the energy delivery algorithms. In another embodiment,referring back to FIG. 4, at least one temperature sensor 282 can belocated in cement source 115 of the system and/or in a distal portion ofthe injector component 100 for monitoring cement temperature in a cementflow within the system 10.

In another embodiment, a bone treatment system 10 can include a thermalenergy emitter 110 that can deliver energy to a bone cement within thesystem, a controller 145 that can modulate applied energy from theemitter to control a curing reaction of the cement, and a sensor systemoperatively coupled to the system 10 for measuring an operationalparameter of bone cement 130 within the system 10. In FIG. 6, it can beseen that a sensor of the sensor system may include a temperaturesensor, indicated at 270, which is disposed on or in controller 145. Thetemperature sensor 270 of the controller 145 may allow for input ofcontrol algorithms into the system 10 for modulating applied energy fromthe emitter 110 that are dependent on ambient air temperature in theoperating room environment. Such control algorithms may be ofsignificant utility, as the ambient temperature of an operating room canaffect the time-viscosity curve of an exothermic PMMA-based bone cement.

In some embodiments, the bone cement system 10, and more particularly,the cement mixing assembly 275 of FIG. 6 may include a sensor, switch,or indication mechanism 285 for indicating an approximate time ofinitiation of bone cement mixing. Such a sensor or indication mechanism285 can include any manually-actuated mechanism coupled to thecontroller, a mechanism that senses the disposition of the cementprecursors in the mixing assembly or the actuation of any moveablemixing component of the assembly, and combinations thereof. The systemand controller 145 may, in this manner, provide one or more of visual,aural, and/or tactile signals indicating that a selected mixing timeinterval has been reached. This signal may enable consistent measurementof the time at which mixing of the bone cement is completed, alsoreferred to as the zero post-mixing time, such that the viscosity atthis time may be similar in all cases. Beneficially, by precise,consistent measurement of the zero post-mixing time, energy may beproperly applied as described above. The system also can include asensor, switch or indication mechanism 288 that can indicate thetermination of bone cement mixing, and thus time zero on atime-viscosity curve as in FIG. 9, which may be used for setting thealgorithms in the controller 145 for controlling applied energy and thecement flow rate.

In another embodiment, the bone cement system 10 may include a sensorthat measures and indicates the bone cement flow rate within the flowpassageway in the injector system 100. In the embodiment of FIG. 6, amotor drive system 211 can drive the cement via the hydraulic system ata substantially constant rate through the injector and emitter 110. Asshown, a sensor 290 may be operatively coupled to the motor drive 211which can measure the force being applied by the drive to cause thedesired cement flow through the system, which can in turn be used tosense any tendency for a slow-down in the desired flow rate, for exampledue to an unanticipated increase in viscosity of the bone cement in thesystem 10. Upon such sensing, the controller 145 can increase the flowrate or decrease the applied energy from emitter 110 to allow a selectedcement viscosity and flow rate from the injector 100 into bone to bemaintained.

Bone cements 130, in combination with the system 10 may allow forselected working times of the bone cement. Examples of such workingtimes may include, but are not limited to, at least about 6 minutes, atleast about 8 minutes, at least about 10 minutes, at least about 12minutes, at least about 14 minutes, at least about 16 minutes, at leastabout 18 minutes, at least about 20 minutes, and at least about 25minutes.

In some embodiments, a bone treatment system may include: a first andsecond energy source for causing a controlled curing reaction in a bonecement. The first source may include an exothermic curing reaction whichcan occur in response to mixing cement precursor components. The secondsource can include a thermal energy emitter capable of applying energyto the bone cement in order to vary an exothermic curing reaction of thebone cement. The system may further include a controller capable ofmodulating the applied energy from the emitter to thereby control theexothermic curing reaction over a selected working time. The controllercan be capable of modulating applied energy to provide a selected bonecement viscosity over a working time of at least about: 2, 4, 6, 8, 10,12, 14, 16, 18, 20, and 25 minutes.

In some embodiments the control system 10 may allow for application ofenergy to a bone cement so as to provide a bone cement that possesses aselected cement viscosity range as it exits the injector outlet 122 overthe selected working time. In certain embodiments, the selectedviscosity range may include, but is not limited to, about: 600, 800,1000, 1200, 1400, 1600, 1800, 2000, 2500, 3000, and 4000 Pa·s.

According to some methods, preparing a curable bone cement for injectioninto a vertebra may be provided. The methods can include: mixing bonecement precursors so as to enable a curing reaction to take place in thebone cement and applying energy to the bone cement from an externalsource so as to provide energy to the bone cement. The energy appliedfrom the external source may be controlled by a controller incombination with the curing reaction so as to provide a selected cementviscosity.

Embodiments of a method may further include varying the amount of energyapplied from the external source in response to a selected length of apost-mixing interval. Embodiments of a method may include varying theamount of applied energy from the external source in response to ambienttemperature that is measured by a temperature sensor in the system.

Further, embodiments of a method may include varying the applied energyfrom the external source in response to a selected injection rate of thebone cement flow through the system 10. Embodiments of a method mayinclude varying the applied energy from the external source so as toprovide a bone cement having an injection viscosity of at least about:500, 1000, 1500, 2000, 3000 and 4000 Pa·s.

In further embodiments the control system may allow for application ofenergy to a bone cement so as to provide a bone cement that possesses asubstantially constant cement viscosity over the selected working time.

In still further embodiments the control system 10 may allow for theapplication of energy to a bone cement so as to provide a bone cementthat possesses a plurality of selected time-viscosity profiles of thecement as it exits the injector 100. For example, the controller 145 andenergy emitter 110 may be capable of applying energy to the bone cementin an amount that is sufficient to very rapidly increase the viscosityof the bone cement to a selected viscosity that will inhibitextravasation.

As can be seen in the time-viscosity curve 260 of FIG. 8B, embodimentsof the system 10 and the bone cement 130 discussed herein may beemployed to provide a bone cement whose viscosity can be elevated toabove about 2000 Pa·s within about 15-30 seconds. It can be understoodthat a method may include utilizing an energy emitter 110 that appliesenergy to bone cement to controllably increase its viscosity to at least200 Pa·s, at least 500 Pa·s or at least 1,000 Pa·s in less than 2minutes or less than 1 minute. Alternatively, a method of bone cementtreatment may include utilizing an energy emitter that applies energy tobone cement to controllably increase the viscosity to at least 1,000Pa·s, at least 1,500 Pa·s, at least 2,000 Pa·s or at least 2,500 Pa·s inless than 2 minutes or less than 1 minute.

In some embodiments, a method of preparing a curable bone cement forinjection into a vertebra may be provided that allows a bone cement toexhibit a selected time-viscosity profile. A method may include: mixingbone cement precursors so as to cause a curing reaction characterized bya first time-viscosity profile of the bone cement, actuating an energycontroller so as to controllably apply energy to the bone cement from anexternal energy source so as to cause the bone cement to adopt a secondtime-viscosity profile, different from the first time-viscosity profile,and injecting the cement characterized by the cement secondtime-viscosity profile into the vertebra. In some embodiments of thismethod, the cement viscosity may be at least about 500 Pa·s, at leastabout 1000 Pa·s, at least about 1500 Pa·s, at least about 2000 Pa·s, atleast about 3000 Pa·s, or at least about 4000 Pa·s. Some embodiments ofthe method may further include actuating the controller to modulateapplied energy in response to control signals including, but not limitedto, the length of a cement post-mixing interval, the ambienttemperature, the bone cement temperature, and rate of bone cementinjection into the vertebra.

Looking now at FIG. 10, a schematic, graphical representation of thetime-viscosity response, 250 and 255, respectively, of an embodiment ofthe bone cement of FIG. 8A after mixing at ambient temperatures of about22° C. and 18° C. is shown. It can be seen that different levels ofenergy may be applied to achieve a similar time-viscosity curve 260. Forexample, less energy may be applied to bone cement at 22° C. than isapplied to the bone cement at 18° C. in order to achieve thetime-viscosity response 260, as the higher temperature bone cement,prior to energy application, contains more energy than lower temperaturebone cement. Methods may further include providing inputs into thecontrol algorithms for controlling applied energy to cement flows thatfactor in ambient temperatures.

In one embodiment, the system 10 may be employed in order to provide thebone cement 130 with a working time for polymerizing from an initialstate to a selected endpoint of at least about 10 minutes, at leastabout 12 minutes, at least about 14 minutes, at least about 16 minutes,at least about 18 minutes, at least about 20 minutes, at least about 25minutes, at least about 30 minutes and at least about 40 minutes, asdisclosed in U.S. Provisional Application No. 60/899,487. In anembodiment of the present disclosure, the initial state may include afirst selected viscosity range of the bone cement 130 within about 90 to600 seconds after completion of mixing of the bone cement components. Inanother embodiment of the disclosure, the selected endpoint of the bonecement 130 may include a second selected viscosity range thatsubstantially inhibits bone cement extravasation. Herein, the terms“polymerization rate” and “working time” may be used alternatively todescribe aspects of the time interval over which the cement polymerizesfrom the initial state to the selected endpoint.

As can be understood from FIGS. 1-6, the energy source 140 may also becapable of applying energy to the bone cement 130 via the emitter 110and accelerating a polymerization rate of the bone cement 130 by atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90% and at least about 95%, as compared to thepolymerization rate achieved absent this application of energy. Inanother embodiment of the present disclosure, the energy source 140 andcontroller 145 may be capable of accelerating the polymerization rate ofthe bone cement 130 to the selected endpoint in less than about 1second, less than about 5 seconds, less than about 10 seconds, less thanabout 20 seconds, less than about 30 seconds, less than about 45seconds, less than about 60 seconds and less than about 2 minutes.

An embodiment of a method of using the system 10 of FIGS. 1-6 to treat avertebra is also provided. The method can include a first operation ofintroducing a cement injector needle into a vertebra. The needle mayinclude a flow channel extending from a proximal injector end to adistal injector end possessing a flow outlet. The method may furtherinclude a second operation of causing a flow of bone cement from thebone cement source through a flow channel in an energy-deliverycomponent and the injector needle. The method may additionally includeapplying energy from the energy-delivery component to the flow of bonecement so as to cause a change in the setting rate of the cement so asto reach a selected polymerization endpoint. In this method, the appliedenergy may accelerate setting of a bone cement before it exits the flowoutlet of the injector. The method and the selected polymerizationendpoint can advantageously provide a viscosity that substantiallyprevents cement extravasation following introduction into the vertebra.

In another embodiment, referring to FIG. 11, a bone cement system 400may include a first and a second thermal energy emitter for controlledapplication of energy to a bone cement flow within the flow passageway112 of the injector system 100. More particularly, a first emitter 110is shown disposed in the first handle component 105 as describedpreviously. A second emitter 410 may be disposed in a medial or distalportion of the second extension component 124 of the injector system100. A controller 145 may be capable of modulating applied energy fromthe first and second emitters, 110 and 410, to provide a controlledcuring reaction of the flow of bone cement 130. In one method of use,the first emitter 110 can apply energy to warm the flow of cement toaccelerate polymerization so that the selected flow rate carries thecement 130 to the location of the second emitter 410 at a viscosity ofless than about 500 to 1000 Pa·s and, thereafter, the applied energy ofthe second emitter 410 may increase the viscosity of the bone cement 130to greater than about 2000 Pa·s. In this manner, the bone cementviscosity within the flow channel 112 can be kept at a level that can bepushed with a low level of pressure and the final viscosity of the bonecement exiting the outlet 122 can be at a relatively high viscosity, forexample, at a level capable of fracturing cancellous bone, such asgreater than about 2000 Pa·s. It should be recognized that theviscosities given above are examples, the particular viscosity of theflow from the emitters 110 and 410 can depend on many factors, includingthe cement used, the treatment being performed, etc.

FIG. 11 further illustrates electrical connector components 414 a and414 b provided in the interface between the first and second components,100 and 105. These electrical connector components 414 a, 414 b canprovide an electrical connection from electrical source 140 to theemitter 410 via electrical wires indicated at 416 in the handle portion105 of the system. It may be appreciated that the second emitter 410 caninclude a PTCR emitter, as described previously, or any other type ofheating element. The heating element can have any length including theentire length of the extension portion 124. In one embodiment, theemitter 110 in handle component 105 has a length of less than about 50mm and can carry a volume of cement that is less than about: 1.0 cc, 0.8cc, 0.6 cc, 0.4 and 0.2 cc.

In another embodiment of a method, the energy-delivery emitter 110 maybe actuated by the operator from a location outside any imaging field.The cable 214 carrying an actuation switch 212 can be any suitablelength, for example about 10 to 15 feet in length (see FIG. 6).

In another embodiment of a method, the energy-delivery emitter 110 maybe actuated to apply energy of at least about: 0.01 Watt, 0.05 Watt,0.10 Watt, 0.50 Watt and 1.0 Watt. In another embodiment of a method,the applied energy may be modulated by a controller 145. In anotherembodiment of a method, the energy source 140 and controller 145 may becapable of accelerating the polymerization rate of the bone cement 130to the selected endpoint in less than 1 second, 5 seconds, 10 seconds,20 seconds, 30 seconds, 45 seconds, 60 seconds and 2 minutes. In anotherembodiment of a method, the energy source 140 and controller 145 may becapable of applying energy to a bone cement composition 130 foraccelerating the polymerization rate of the bone cement 130 by at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90% and at least about 95%, as compared to the polymerization rateabsent the applied energy.

In certain embodiments, a method of bone cement injection is alsoprovided. The method includes modulating a rate of bone cement flow inresponse to a determination of a selected parameter of the cement flow.Examples of the selected parameter may include the flow rate of the bonecement. A method of bone cement injection can further include applyingthermal energy to the bone cement and modulating the thermal energyapplication from an emitter in the injector body to the cement flow.Some methods of bone cement injection can further include modulating theapplication of energy in response to signals that relate to a selectedparameter, such as the flow rate of the cement flow.

In another embodiment, a method of bone cement injection can include (a)providing a bone cement injector body carrying a PTCR (positivetemperature coefficient of resistance) material in a flow channeltherein, (b) applying a selected level of energy to a bone cement flowthrough the PTCR material, and (c) utilizing an algorithm that processesimpedance values of the PTCR material to determine the bone cement flowrate. The method of bone cement injection may further include modulatinga cement injection parameter in response to the processed impedancevalues. Examples of the cement injection parameter may include, but arenot limited to flow rate, pressure, and power applied to the flow.

Another embodiment of a method of bone cement injection can include: (a)providing a bone cement injector body carrying a PTCR material or otherthermal energy emitter in a flow channel therein, (b) causing bonecement to flow through the flow channel at a selected cement flow rateby application of a selected level of energy delivery to the cement flowthrough the emitter, and (c) modulating the selected flow rate and/orenergy delivery to maintain a substantially constant impedance value ofthe emitter material over a cement injection interval. The selectedcement injection interval can include at least about 1 minute, at leastabout 5 minutes, at least about 10 minutes, and at least about 15minutes.

In another embodiment, a method can modulate the selected flow rateand/or energy delivery to maintain a substantially constant viscosity ofbone cement ejected from the injector over a selected cement injectiontime interval. The time interval may include from about 1 minute to 10minutes. The system and energy source can be configured for applyingenergy of at least: 0.01 Watt, 0.05 Watt, 0.10 Watt, 0.50 Watt and 1.0Watt. In another embodiment, the energy source 140 and controller 145can be capable of accelerating the polymerization rate of the bonecement to a selected endpoint in less than about: 1 second, 5 seconds,10 seconds, 20 seconds, 30 seconds, 45 seconds, 60 seconds and 2minutes.

Another embodiment of a method of bone cement injection may utilizeembodiments of the systems 10 and 400 as described above. Such methodsmay include (a) providing a bone cement injector body with a flowchannel extending therethrough from a proximal handle end though amedial portion to a distal end portion having a flow outlet, (b) causingcement flow through the flow channel, and (c) warming the cement flowwith an energy emitter in a proximal end or medial portion thereof toinitiate or accelerate polymerization of the cement of the cement flow.The method may further include providing a flow rate of the cement flowthat ranges from about 0.1 cc/minute to 20 cc/minute, from about 0.2cc/minute to 10 cc/minute and from about 0.5 cc/minute to 5 cc/minute.

Embodiments of the above-described method of bone cement injection canallow a predetermined cement flow rate to provide a selected interval inwhich the cement flows are allowed to polymerize in the flow channeldownstream from the energy emitter. This method may include providing aselected interval of greater than about 1 second, greater than about 5seconds, greater than about 10 seconds, greater than about 20 seconds,and greater than about 60 seconds.

The above-described method can utilize an energy emitter that appliesenergy sufficient to elevate the temperature of the bone cement 130 byat least about 1° C., at least about 2° C. and at least about 5° C. Themethod of bone cement injection can include utilizing an energy emitterthat applies at least about 0.1 Watt of energy to the cement flow, atleast about 0.5 Watt of energy to the cement flow, and at least about1.0 Watt of energy to the cement flow. The method may include adjustmentof the flow rate of the bone cement flow in intervals by controller 145,or being continuously adjusted by a controller 145.

In another embodiment of a method, a bone cement injection system asdescribed herein, can utilize a controller 145 and algorithms forapplying energy to bone cement flows to allow the bone cement 130exiting the injector to possess a selected temperature that is higherthan the ambient temperature of the injector. This ability reflects thefact that polymerization has been accelerated, thus reducing the amountof total heat released into bone. More particularly, the method caninclude injecting a settable bone cement into bone after mixing a firstcomponent and a second component of the bone cement, thereby initiatinga chemical reaction to initiate setting of the bone cement, acceleratingthe polymerization with applied energy from an external source, andejecting the bone cement from an injector portion positioned in bone.The bone cement, upon ejection, may possess a temperature greater thanambient temperature of the injector. The method can further includeejecting the bone cement from a terminal portion of an injectorpositioned in bone at a temperature of at least about: 28° C., 30° C.,32° C., 34° C., 36° C., 38° C., 40° C., 42° C., 44° C., 46° C., 48° C.,50° C., 52° C., 54° C., 56° C., 58° C., 60° C., 62° C., 64° C., 66° C.,68° C., 70° C., 72° C., 74° C., 76° C., 78° C. and 80° C.

In another embodiment, a method of injecting a bone cement into bone caninclude mixing first and second bone cement components, thereby causingan exothermic chemical reaction which results in a thermal energyrelease. The method may further include actuating an injector controlsystem capable of controlling the temperature of the bone cement beforethe bone cement contacts bone. In general, the actuating step caninclude (i) controlling the flow rate of the bone cement within a flowpassageway of an injector system, (ii) controlling the application ofenergy to the bone cement from an emitter operatively coupled to anenergy source, and (iii) controlling the driving force applied to theflow of bone cement which may benefit from adjustment based on the bonecement viscosity.

The actuating step can also include sensing an operating parameter ofthe bone cement flow to which the controller is responsive. Theoperating parameter can include the bone cement flow rate, the bonecement temperature, the driving force applied to the cement flow, theenergy applied to the cement from an emitter coupled to an energy sourceand cement viscosity and environmental conditions, such as temperatureand humidity in the environment ambient to the injector system. Thus,the controller 145 can be capable of modulating the flow rate,modulating the applied energy, and/or modulating the driving force inresponse to sensing any one or more of the above operating parameters.

In another embodiment, a method of injecting a bone cement is provided.The method can include mixing first and second bone cement components soas to cause an exothermic chemical reaction that results in a thermalenergy release. The method can also include actuating an injectorcontrol system which is capable of controlling the amount of thermalenergy released from the cement before the bone cement contacts bonetissue to thereby reduce the thermal energy released into the bone.

The thermal energy released from the cement may be directly related tothe level of polymerization acceleration from the applied energy, aswell as the dwell time of the cement within the flow channel before thecement exits the outlet in a terminal portion of the injector. The dwelltime of the cement in the flow channel can be controlled by controller145 as described above, where at least one of the flow rate and drivingforce applied to the cement flow can be modulated. In the systemembodied in FIGS. 1-6, the application of energy by emitter 110 incomponent 105 can provide for a dwell time within the flow channel 112before exiting outlet 122 for a flow interval of at least about: 5seconds, 10 seconds, 20 seconds, 30 seconds, 40 seconds and 60 seconds.This method of conditioning and injecting bone cement can allow athermal energy release from the bone cement before the bone cementcontacts bone of at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45% and at least about 50%.

In another embodiment, it can be understood that the systems and methodsdisclosed herein may be further employed in order to control the amountof thermal energy released from the bone cement before the cementcontacts bone tissue to thus reduce the amount of thermal energyreleased into the bone.

For example, in one embodiment, a method of injecting a bone cement cancontrol the amount of thermal energy released by the bone cement beforethe bone cement contacts bone tissue. The method includes controlling aninjector control system that is capable of controlling the rate ofchemical reaction before the bone cement contacts bone tissue. Thereaction rate can be adjusted by the controller such that the maximumcomposition temperature is reached when the cement is within the flowchannel of the injector system, prior to reaching the bone tissue.Beneficially, in this manner, the amount of total thermal energyreleased by the bone cement is released while the bone cement is stillwithin the flow channel of the injector system, before the bone cementcontacts the bone tissue. This method substantially reduces the amountof thermal energy which is released by the bone cement into the bonetissue.

In another method of injecting bone cement, the actuating step caninclude allowing at least about 10% of the total thermal energy releasedfrom a bone cement to be released while the bone cement flows within theinjector system. In certain embodiments, such energy release may beaccomplished by providing a mean cement flow rate of at least about 0.1cc/min, at least about 0.5 cc/min, at least about 1.0 cc/min, at leastabout 1.5 cc/min, at least about 2.0 cc/min and at least about 2.5cc/min during heating within the bone cement injector. The method mayfurther include maintaining the bone cement within the cannula for atleast about 20 seconds after being heated.

In another method, the actuating step can allow at least about 10% ofthe total thermal energy released from a bone cement to flow over a flowdistance within the flow channel 112 of the injector system, of at leastabout 5 mm, at least about 10 mm, at least about 20 mm, at least about30 mm, at least about 40 mm, at least about 50 mm, at least about 60 mm,at least about 70 mm, at least about 80 mm, at least about 90 mm and atleast about 100 mm.

In certain embodiments, the methods described above can apply energy toa selected volume of a bone cement mixture. A selected amount of thermalenergy from the exothermic reaction of the bone cement components may bereleased within the flow channel so as to inhibit a selected portion ofthe thermal energy from reaching a patient's bones. Beneficially, inthis manner, a reduction in the thermal effects in the bone due tointroduction of the bone cement within the bone may be achieved.Embodiments of the method can include selecting first and second bonecement components, or precursors, that result in a peak temperature ofthe bone cement composition during curing of less than about: 75° C.,70° C., 65° C. and 60° C. Embodiments of such bone cements may includethose bone cements described herein. In certain embodiments, theinjected volume subjected to the accelerated chemical reaction releasesless thermal energy than a cement mixture not subjected to theaccelerated chemical reaction, wherein the release is at least about:10%, 20%, 30%, 40% and 50% less thermal energy release than a cementmixture not subjected to the accelerated chemical reaction.

Thus, from the above disclosure, it can be understood that someembodiments of bone cement injection systems can include first andsecond bone cement components, or precursors, that, upon mixing, resultin a chemical reaction that sets the cement mixture. The bone cementinjection system can further include an injector system that may includea drive system for inducing flow of the cement mixture through thesystem and into bone. The bone cement injection system can furtherinclude an energy emitter for applying energy to the cement mixture inthe injector system to thereby accelerate the chemical reaction betweenthe first and second bone cement components therein. The bone cementinjection system may also include a controller, operatively coupled toat least one of the drive system and energy emitter, for controlling theacceleration of the chemical reaction in the bone cement. In oneembodiment, the first and second bone cement components, or precursors,may possess a post-mixing peak temperature of less than about: 75° C.,70° C., 65° C. and 60° C. The drive system and controller may further becapable of controllably applying a driving force to the cement mixturein the injector system of at least about: 500 psi, 1,000 psi, 1,500 psi,2,000 psi, 2,500 psi, 3,000 psi, 3,500 psi, 4,000 psi, 4,500 psi and5,000 psi.

In one embodiment, the drive system and controller can be capable ofcontrollably maintaining a substantially constant flow rate of thecement mixture. Examples of the flow rate control may include, but arenot limited to, flow rate variations that are within less than about: 1%variation; 5% variation; 10% variation and 15% variation.

In one embodiment, the drive system and controller can be capable ofcontrolling a mean cement mixture flow rate. The mean cement flow ratemay include at least about 0.1 cc/min, at least about 0.5 cc/min, atleast about 1.0 cc/min, at least about 1.5 cc/min, at least about 2.0cc/min and at least about 2.5 cc/min.

The energy emitter and controller may further be capable of controllablyapplying energy to the cement mixture. In certain embodiments thecontroller may provide at least about: 20 joules/cc, 40 joules/cc, 60joules/cc, 80 joules/cc, 100 joules/cc, 120 joules/cc, 140 joules/cc,160 joules/cc and 180 joules/cc.

In certain embodiments, a bone cement injection system can include anenergy emitter and controller capable of providing a dynamic or apre-programmed adjustment of applied energy to the cement mixture inresponse to a signal indicative of the flow rate of the cement mixture.The signal, in certain embodiments, may include a feedback signal to thecontroller 145 indicative of at least one of the temperature of thecement mixture, the viscosity of the cement mixture, the flow rate ofthe cement mixture and the driving force applied to the cement mixture,at least one environmental condition and combinations thereof.

Further embodiments of the present disclosure relate to bone cementcompositions and formulations for use in the bone cement deliverysystems described above. The bone cement formulations can provide for anextended working time, since the viscosity of the bone cement can bealtered and increased on demand when injected.

Bone cements, such as polymethyl methacrylate (PMMA), have been used inorthopedic procedures for several decades, with initial use in the fieldof anchoring endoprostheses in a bone. For example, skeletal joints,such as in the hip, have been replaced with a prosthetic joint. Aboutone million joint replacement operations are performed each year in theU.S. Frequently, the prosthetic joint may be cemented into the boneusing an acrylic bone cement, such as PMMA. In recent years, bonecements also have been widely used in vertebroplasty procedures wherethe cement is injected into a fractured vertebra to stabilize thefracture and eliminate micromotion that causes pain.

Polymethyl methacrylate bone cement, prior to injection, can include apowder component and a liquid monomer component. The powder componentcan include granules of methyl methacrylate or polymethyl methacrylate,an X-ray contrast agent and a radical initiator. Typically, bariumsulfate or zirconium dioxide is used as an X-ray contrast agent. Benzoylperoxide (BPO) is typically used as radical initiator. The liquidmonomer component typically consists of liquid methyl methacrylate(MMI), an activator, such as N,N-dimethyl-p-toluidine (DMPT) and astabilizer, such as hydroquinone (HQ). Prior to injecting PMMA bonecements, the powder component and the monomer component are mixed andthereafter the bone cement hardens within several minutes followingradical polymerization of the monomer.

Typical bone cement formulations (including PMMA formulations) used forvertebroplasty have a fairly rapid cement curing time after mixing ofthe powder and liquid components. This allows the physician to spendless time waiting for the cement to increase in viscosity prior toinjection. Further, the higher viscosity cement is less prone tounwanted extravasation which can cause serious complications. Thedisadvantage of such current formulations is that the “working time” ofthe cement is relatively short—for example about 5 to 8 minutes—in whichthe cement is within a selected viscosity range that allows forreasonably low injection pressures while still being fairly viscous tohelp limit cement extravasation. In some bone cement formulations, theviscosity ranges between approximately 50 to 500 N s/m² and is measuredaccording to ASTM standard F451, “Standard Specification for AcrylicBone Cement,” which is hereby incorporated by reference in its entirety.

In some embodiments, a bone cement provides a formulation adapted foruse with the cement injectors and energy delivery systems describedabove. These formulations are distinct from conventional formulationsand have greatly extended working times for use in vertebroplastyprocedures with the “on-demand” viscosity control methods and apparatusdisclosed herein and in applications listed and incorporated byreference above.

In some embodiments, a bone cement provides a formulation adapted forinjection into a patient's body, wherein the setting time is about 25minutes or more, more preferably about 30 minutes or more, morepreferably about 35 minutes or more, and even more preferably about 40minutes or more. Setting time is measured in accordance with ASTMstandard F451.

In some embodiments, a bone cement, prior to mixing and setting,includes a powder component and a liquid component. The powder componentmay include a PMMA that is about 64% to 75% by weight based on overallweight of the powder component. In this formulation, an X-ray contrastmedium may be further provided in a concentration less than about 50 wt.%, such as about 25 to 35 wt. %, and about 27% to 32 wt. % based onoverall weight of the powder component. The X-ray contrast medium, inone embodiment, may include barium sulfate (BaSO₄) or zirconium dioxide(ZrO₂). In one embodiment, the formulation may further include BPO thatis about 0.4% to 0.8% by weight based on overall weight of the powdercomponent. In another embodiment, the BPO is less than about 0.6 wt. %,less than about 0.4 wt. % and less than about 0.2 wt. % based on overallweight of the powder component. In such formulations, the liquidcomponent may include MMA that is greater than about 99% by weight basedon overall weight of the liquid component. In such formulations, theliquid component may also include DMPT that is less than about 1% byweight based on overall weight of the liquid component. In suchformulations, the liquid component may also include hydroquinone thatranges between about 30 and 120 ppm of the liquid component. In suchformulations, the liquid weight/powder weight ratio may be equal to orgreater than about 0.4. In such formulations, the PMMA may includeparticles having a mean diameter ranging from about 25 microns to 200microns or ranging from about 50 microns to 100 microns.

In certain embodiments, the concentrations of benzoyl peroxide and DMPTmay be varied in order to adjust setting times. Studies examining theinfluence of bone cement concentration on setting times (FIG. 12) havedemonstrated that, in bone cements comprising BPO and DMPT, increases inBPO and DMPT concentration increase the set time of the bone cement. Thedata further illustrate that, of the two bone cement constituents, BPOmay exert a greater rate of effect on set time than does DMPT. Thus, incertain embodiments of a bone cement composition, the concentration ofBPO, DMPT, and combinations thereof, may be increased within the rangesdiscussed above so as to increase the setting time of the composition.

The setting time of the cement may also be influenced by applying energyto the bone cement composition. As discussed above, embodiments of theinjector system of FIGS. 1-6 & 11 may be configured to deliver energy tothe bone cement composition. In certain embodiments, the applied energymay heat the bone cement composition to a selected temperature.

FIG. 13 illustrates temperature as a function of time from initialmixing for one embodiment of the bone composition so injected. The solidline of FIG. 13 represents the behavior of the bone cement compositionwhen it is not heated by the injector system, referred to ascondition 1. It is observed that, under condition 1, the compositionexhibits three regimes. The first regime is low heating rate regime,where the temperature of the composition increases modestly with time.In this regime, the composition begins to slowly self-heat due to theonset of a chemical reaction between at least a portion of itscomponents. The second regime is a high heating rate regime, where thechemical reaction causes the composition temperature to rise sharply.Once the temperature of the composition peaks, the composition enters athird, cooling regime, during which the temperature of the compositiondecreases back to room temperature.

The dotted line of FIG. 13 represents the behavior of the compositionwhen it is heated by the injector system, referred to as condition 2. Incontrast to condition 1, four regimes of behavior are exhibited by thecomposition under condition 2. The first, low heating rate regime, thesecond, high heating rate regime, and the third, cooling regime, areagain observed. In contrast with condition 1, however, a new, injectorheating regime, is observed between the first and second regimes. Thisnew regime exhibits a rapid increase in the composition temperature dueto injector heating of the composition. Although the compositiontemperature is observed to peak and fall towards the end of the durationof this regime, the temperature does not fall back to the same level asobserved under condition 1 at about the same time. Therefore, when thesecond, high heating rate regime is entered, the temperature of thecomposition under condition 2 is greater than that under condition 1 andthe composition temperature rises to a peak temperature which is greaterthan that achieved under condition 1.

The setting time of the compositions under conditions 1 and 2 can bemeasured according to ASTM standard F451 and compared to identifychanges in setting time between the two conditions. It is observed thatthe setting time of the composition under condition 1 is approximately38 minutes, while the setting time of the composition under condition 2is approximately 28 minutes, a reduction of about 10 minutes. Thus, byheating the bone cement, the setting time of embodiments of the bonecement composition may be reduced.

From the forgoing, then, it can be appreciated that by varying the BPOand/or DMPT concentrations of the bone cement composition, or by heatingthe bone cement composition, the setting time of the bone cement may beincreased or decreased. Furthermore, in certain embodiments, theconcentration of BPO and/or DMPT in the bone cement may be varied andthe composition may be heated so as to adjust the setting time to aselected value. As discussed above, in certain embodiments, the settingtime is selected to be about 25 minutes or more, more preferably about30 minutes or more, more preferably about 35 minutes or more, and evenmore preferably about 40 minutes or more.

Embodiments of a bone cement composition may further be heated using theinjector systems described herein in order to alter the viscosity of thecomposition. FIG. 14 illustrates measurements of viscosity as a functionof time for an embodiment of the bone cement compositions heated totemperatures ranging between about 25° C. to 55° C. It may be observedthat the bone cement at the lowest temperature, 25° C., exhibits theslowest rate of viscosity increase, while the bone cement at the highesttemperature, 55° C., exhibits the highest rate of viscosity increase.Furthermore, at intermediate temperatures, the bone cement exhibitsintermediate rates of viscosity increase.

From the behavior of condition 1 in FIG. 13, it can be seen that thepeak temperature of the bone cement composition is higher when thecement is heated by the injector system. Furthermore, by adjusting theenergy output of the injector system, the temperature to which the bonecement rises may be varied. Thus, embodiments of the injector system maybe employed to deliver bone cements having selected levels of viscosity.

In one embodiment, a bone cement has a first component comprisinggreater than about 99 wt. % methyl methacrylate (MMA), less than about 1wt. % N,N-dimethyl-p-toluidine (DMPT), and about 30 to 120 ppmhydroquinone on the basis of the total amount of the first component,and a second component comprising a powder component comprising lessthan about 75 wt. % PMMA, less than about 50 or 32 wt. % of an X-raycontrast medium, and benzoyl peroxide (BPO).

In certain embodiments, the composition may further include less thanabout 0.4 wt. % (BPO) on the basis of the total weight of the secondcomponent. In further embodiments, the composition may include about 0.2to 0.3 wt. % BPO on the basis of the total weight of the secondcomponent. In other embodiments, the second component has less thanabout 0.2 wt. % benzoyl peroxide (BPO) on the basis of the total weightof the second component, or less than about 0.1 wt. % benzoyl peroxide(BPO) on the basis of the total weight of the second component. In sucha formulation, the liquid weight/powder weight ratio may be equal to orgreater than about 0.4.

In one embodiment, a bone cement may include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. The bone cement mixture, aftermixing, may be characterized by having a viscosity of less than about500 Pa·s at about 18 minutes post-mixing. The bone cement further can becharacterized as having a time-viscosity curve slope of less than about200 Pa·s/minute for at least about 5 minutes after reaching a viscosityof about 500 Pa·s. The bone cement further can be characterized by apost-mixing time-viscosity curve slope of less than 100 Pa·s/minute forat least about 15 minutes, at least about 16 minutes, at least about 17minutes, at least about 18 minutes, at least about 19 minutes, and atleast about 20 minutes.

In one embodiment, a bone cement can include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. Post-mixing, the bone cementmixture may be characterized by a time-viscosity curve having a slope ofless than about 100 Pa·s/minute until to the mixture reaches a viscosityof about 500 Pa·s. In other embodiments, the bone cement, post-mixing,can be characterized by a time-viscosity curve slope of less than about100 Pa·s/minute immediately before the mixture reaches a viscosity ofabout 800 Pa·s. In this context, immediately may refer to a time periodless than about 30 seconds. In other embodiments, the bone cementfurther can be characterized by a time-viscosity curve slope of lessthan about 100 Pa·s/minute immediately before the mixture reaches aviscosity of about 1000 Pa·s. In other embodiments, the bone cementfurther can be characterized by a time-viscosity curve slope of lessthan about 100 Pa·s/minute immediately before the mixture reaches aviscosity of about 1500 Pa·s.

In other embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than about 200 Pa·s/minuteimmediately before the mixture reaches a viscosity of about 500 Pa·s. Inother embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than about 200 Pa·s/minuteimmediately before the mixture achieves a viscosity of about 1000 Pa·s.In other embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than about 200 Pa·s/minuteimmediately before the mixture achieves a viscosity of about 1500 Pa·s.In other embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than 200 Pa·s/minute immediatelybefore the mixture achieves a viscosity of about 2000 Pa·s, about 3000Pa·s and about 4000 Pa·s.

In one embodiment, a bone cement may include a first monomer-carryingcomponent and a second polymer-carrying component, wherein post-mixingthe mixture is characterized by a change of viscosity of less than about20% over an interval of at least about 5 minutes, at least about 10minutes, at least about 15 minutes, and at least about 20 minutes. Inother embodiments, the mixture may be characterized by a time-viscositycurve having a rate of change less than about 40% over an interval of atleast about 5 minutes, at least about 10 minutes, at least about 15minutes, and at least about 20 minutes.

In one embodiment, the bone cement may include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing, the mixture of the first and second components may becharacterized as having a viscosity of less than about 100 Pa·s at about10 minutes post-mixing, less than about 200 Pa·s at about 15 minutespost-mixing, or less than about 500 Pa·s at about 18 minutespost-mixing.

In one embodiment, the bone cement may include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing, the mixture may receive applied energy of at least about 20joules/cc, at least about 40 joules/cc, at least about 60 joules/cc, atleast about 80 joules/cc, at least about 100 joules/cc, at least about120 joules/cc, at least about 140 joules/cc, at least about 160joules/cc, and at least about 180 joules/cc without substantiallysetting in an interval of less than about 10 minutes. In otherembodiments, the bone cement, after mixing, may possess a viscositygreater than about 500 Pa·s within about 10 seconds, about 30 seconds,about 60 seconds, about 90 seconds, about 120 seconds, about 180seconds, and about 240 seconds of application of energy from an externalsource of at least about 60 joules/cc.

In certain embodiments, the cement mixture of the precursors may becharacterized by a post-mixing interval in which viscosity is betweenabout 500 Pa·s and 5000 Pa·s, and in which the change of viscosity ofless than about 30%/minute. In another embodiment, the settable bonecement includes first and second cement precursors, where the cementmixture of the precursors is characterized by a post-mixing interval inwhich the viscosity of the mixture is between about 500 Pa·s and 2000Pa·s, and in which the change of viscosity of the mixture is less thanabout 20%/minute.

In another embodiment, the settable bone cement includes a firstmonomer-carrying component and a second polymer-carrying component, suchas the liquid and powder components discussed above. In certainembodiments, after mixing the first and second components, the mixtureis characterized by a change of viscosity of less than 20%/minute for atleast three minutes after reaching about 500 Pa·s, about 1000 Pa·s,about 1500 Pa·s, and about 2000 Pa·s.

In another embodiment, the cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya change of viscosity of less than 30%/minute for at least three minutesafter reaching about: 500 Pa·s, 1000 Pa·s, 1500 Pa·s and 2000 Pa·s. In arelated embodiment, the cement can include a first monomer-carryingcomponent and a second polymer-carrying component, wherein post-mixingthe mixture is characterized by a change of viscosity of less than40%/minute for at least three minutes after reaching about: 500 Pa·s,1000 Pa·s, 1500 Pa·s and 2000 Pa·s. In a related embodiment, the cementcan include a first monomer-carrying component and a secondpolymer-carrying component, wherein post-mixing the mixture ischaracterized by a change of viscosity of less than 30%/minute for atleast five minutes after reaching about: 1000 Pa·s, 1500 Pa·s, 2000Pa·s, 2500 Pa·s, 3000 Pa·s, 3500 Pa·s and 4000 Pa·s.

In a further embodiment, the cement may include a first monomer-carryingcomponent and a second polymer-carrying component, wherein the mixtureis characterized by a rate of change of viscosity of less than about40%/minute for at least five minutes after reaching about 1000 Pa·s,about 1500 Pa·s, about 2000 Pa·s, about 2500 Pa·s, about 3000 Pa·s,about 3500 Pa·s, and about 4000 Pa·s.

In a related embodiment, a cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya change of viscosity of less than about 50%/minute for at least aboutfive minutes after reaching about 1000 Pa·s, about 1500 Pa·s, about 2000Pa·s, about 2500 Pa·s, about 3000 Pa·s, about 3500 Pa·s, and about 4000Pa·s.

In another embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, themixture is characterized by a rate of change of viscosity of less thanabout 50%/minute after reaching a viscosity of about 5000 Pa·s. In arelated embodiment, a cement includes a first monomer-carrying componentand a second polymer-carrying component, such as the liquid and powdercomponents discussed above. In certain embodiments, after mixing thefirst and second components, the mixture is characterized by a rate ofchange of viscosity of less than about 50%/minute after achieving aviscosity of about 4000 Pa·s. In a related embodiment, a cement includesa first monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, themixture is characterized by a rate of change of viscosity of less thanabout 50%/minute after achieving a viscosity of about 3000 Pa·s.

In another aspect, a cement can include a first monomer-carryingcomponent and a second polymer-carrying component, wherein post-mixingthe mixture is characterized by a rate of change of viscosity of lessthan 50%/minute for an interval preceding the point in time the mixtureachieves about 5000 Pa·s, the interval being at least about: 2, 3, 4, 5,6 and 8 minutes.

In a related embodiment, a cement includes a first monomer-carryingcomponent and a second polymer-carrying component, wherein the mixtureis characterized post-mixing by a rate of change of viscosity of lessthan about 40%/minute for an interval preceding the point in time themixture achieves about 5000 Pa·s, the interval being at least about: 2,3, 4, 5, 6, and 8 minutes.

In a related embodiment, a cement can include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya rate of change of viscosity of less than about 30%/minute for aninterval preceding the point in time the mixture achieves about 5000Pa·s, the interval being at least about: 2, 3, 4, 5, 6, and 8 minutes.

In another embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, themixture is characterized by a post-mixing interval of at least 4minutes, 6 minutes, 8 minutes or 10 minutes in the interval precedingthe point in time the mixture achieves 3000 Pa·s.

In a related embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, ischaracterized by a post-mixing interval of at least about 4 minutes, atleast about 6 minutes, at least about 8 minutes or at least about 10minutes in the interval preceding the point in time the mixture achievesat least about 4000 Pa·s.

In a related embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, ischaracterized by a post-mixing interval of at least about 4 minutes, atleast about 6 minutes, at least about 8 minutes or at least about 10minutes in the interval preceding the point in time the mixture achievesabout 5000 Pa·s.

Now turning FIG. 15, embodiments of bone cement described above can becharacterized by the time-viscosity curves of cements A and B, andcompared with commercially available cements C, D and E. Cement A is abone cement composition of the present disclosure having a PMMA tomonomer ratio of about 2:1. Cement B is also a cement composition of thepresent disclosure having a PMMA to monomer ratio of about 2.5:1. CementC is Mendec Spine bone cement which includes a PMMA to monomer ratio ofabout 2.1:1. D is DePuy Vertebroplasty cement which includes a PMMA tomonomer ratio of about 2.3:1. Cement E is Arthrocare Parallax acrylicresin, which includes a PMMA to monomer ratio of about 2.4:1.

Cement A includes a first monomer-carrying component and a secondpolymer-carrying component, such as the liquid and powder componentsdiscussed above. In certain embodiments, post-mixing, the mixture ischaracterized by a time-viscosity curve slope of less than about 200Pa·s/minute until the mixture achieves a viscosity of about 3000 Pa·s.In another cement embodiment, Cement A may include a firstmonomer-carrying component and a second polymer-carrying component,where, post-mixing, the mixture is characterized by a time-viscositycurve slope of less than about 200 Pa·s/minute until to the mixtureachieves a viscosity of about 2500 Pa·s. Bone cement B includes a firstmonomer-carrying component and a second polymer-carrying component,where, post-mixing, the mixture is characterized by a time-viscositycurve slope of less than about 200 Pa·s/minute for at least about 20minutes, at least about 25 minutes, and at least about 30 minutes.

Beneficially, as compared to the prior art compositions (C, D, E) eachof compositions A and B may be observed to exhibit a relatively longworking time before their slope increases significantly. Furthermore,compositions A and B exhibit a more linear slope than the prior artcompositions, which indicates that the rate of viscosity change withtime is more constant.

In another embodiment of the present disclosure, a settable or curablebone cement is provided that includes two mixable components asdescribed above: a liquid monomer component and a non-liquid component.In this embodiment of bone cement, the non-liquid component may includepolymer beads or particles containing an initiator, for example, BPO.The non-liquid component may be capable of providing controlled exposureof the initiator to the liquid monomer over a selected time intervalduring which the bone cement sets, also referred to as a settinginterval of the bone cement. The controlled exposure of the initiator,such as BPO, to the monomer, can provide control over the time-viscositycurve of a bone cement over a working time of the cement.

Embodiments of cement may be used with the systems disclosed herein,including those shown in FIGS. 1-6 & 11, or may be used in aconventional form of vertebroplasty. Further embodiments of the cementmay be employed with the systems disclosed herein in order to provideany of the physical properties of the cement discussed herein.

In one embodiment, a settable bone cement may include mixable first andsecond components, wherein the first component includes greater thanabout 99 wt. % methyl methacrylate (MMA), and less than about 1 wt. %N,N-dimethyl-p-toluidine (DMPT), about 30 to 120 ppm hydroquinone on thebasis of the total amount of the first component, and wherein the secondcomponent includes a PMMA component that includes less than about 75 wt.% PMMA, less than about 32 wt. % of an X-ray contrast medium; and aselected wt. % of benzoyl peroxide (BPO) on the basis of the totalweight of the second component. More particularly, the PMMA componentmay includes first and second volumes of polymer beads having first andsecond amounts of BPO, respectively.

In one embodiment of bone cement compositions with controlled exposureof BPO, referring to FIG. 16, the desired differential BPO exposure overthe working time of the cement may be provided by polymer beads orparticles and having differing BPO configurations integrated therein.FIG. 16 illustrates first polymer beads 700 of the non-liquid componentwhich have a small diameter and include BPO 704A in a higher densitywhen compared to BPO 704B within second polymer beads 705 of thenon-liquid component of the cement.

In an embodiment, the first polymer beads 700 can have an average crosssection of less than about 100 microns, less than about 80 microns, lessthan about 60 microns, or less than about 40 microns. The first polymerbeads 700 may further include greater than about 0.5 wt. % of BPO, onthe basis of the total weight of the non-liquid component. Stillreferring to FIG. 16, the second polymer beads or particles 705 can havean average cross section of greater than about 40 microns, greater thanabout 60 microns, greater than about 80 microns, and greater than about100 microns, with a less than about 0.5 wt. % of BPO, on the basis ofthe total weight of the non-liquid component. In combination, the firstand second polymer beads or particles 700, 705 may include less thanabout 5.0 wt. % of BPO, on the basis of the total weight of thenon-liquid component.

In another embodiment, the PMMA component includes a first volume ofpolymer beads 700 having greater than about 0.4 wt. % BPO on the basisof the total weight of the PMMA component and the first volume has amean bead diameter of less than about 100 microns. In this embodiment,the PMMA component may include a second volume of polymer beads 705having less than about 0.4 wt. % BPO on the basis of the total weight ofthe PMMA component and the second volume has a mean bead diameter ofgreater than about 100 microns.

In another embodiment, the bone cement may include a plurality ofdifferent PMMA beads of differing sizes, each carrying a BPO. The amountof BPO may be varied, as necessary, between the different PMMA beads. Inanother embodiment, the mean BPO amount contained within the pluralityof beads may range from about 0.3 to 0.6 wt. on the basis of the totalweight of the PMMA.

In another embodiment, the PMMA component may include a first volume ofpolymer beads 700 that has greater than about 0.4 wt. % BPO on the basisof the total weight of the PMMA and the first volume of polymer beads200 has a mean bead diameter of greater than about 100 microns. Further,the PMMA component may include a second volume of polymer beads 705having less than about 0.4 wt. % BPO on the basis of the total weight ofthe PMMA component and the second volume of polymer beads 705 has a meanbead diameter of less than about 100 microns.

In another embodiment of bone cement, FIG. 17, the BPO in the non-liquidcomponent may be included in the form of particles 706 of BPO and BPOparticles 704C integrated into polymer particles 708. The BPO particles706 may possess a mean diameter ranging between about 1 to 40 μm and maybe present within the non-liquid component in a concentration rangingbetween about 0.3 to 2 wt. % on the basis of the total weight of thenon-liquid component. The BPO particles 704C within the polymerparticles 708 may possess a mean diameter ranging between about 0.5 to 5μm and possess a concentration ranging between about 0.1 to 2 wt. % onthe basis of the total weight of the non-liquid component.

In another embodiment, the polymer particles 708 can have regions ofdiffering density of BPO 704C. Examples of densities may include, butare not limited to, about 10,000 to 100,000 particles/cm³ of the polymerparticles 708.

In certain embodiments, BPO particles 706 may be further added to thebone cement composition in combination with the polymer particles 708.The BPO particles 706 may possess a mean diameter ranging between about1 to 40 μm and may be present within the non-liquid component in aconcentration ranging between about 0.3 to 2 wt. % on the basis of thetotal weight of the non-liquid component.

In another embodiment of bone cement, FIG. 18, the BPO configuration inthe non-liquid component can include polymer particles 710 comprisinglayers of BPO. The BPO may be configured as a surface layer 714A whichis present on at least a portion of an exterior surface of the polymerparticles 710. In a further embodiment, one or more BPO layers 714B maybe present within the interior of the polymer particles 710. In anadditional embodiment, one or more surface BPO layers 714A may bepresent upon at least a portion of the surface of the exterior surfaceof the polymer particles 710 and one or more interior BPO layers 714Bmay be present within the interior of the polymer particles 710. Theinterior BPO layers 714B may be positioned at radial distances of about5 to 80 μm from the center of the polymer particles 710. The BPO surfacelayers and interior layers 714A, 714B may possess thicknesses rangingbetween about 0.5 to 30 μm. In alternative embodiments, the volume ofBPO surface coatings and interior layers 714A, 714B may range betweenabout 1×10⁻¹⁰ to 1×10⁻⁴ cm³.

In certain embodiments, BPO particles 706 may be further added to thebone cement composition in combination with the polymer particles 708.The BPO particles 706 may possess a mean diameter ranging between about1 to 40 μm and may be present within the non-liquid component in aconcentration ranging between about 0.3 to 2 wt. % on the basis of thetotal weight of the non-liquid component.

In further embodiments, the BPO configuration in the non-liquidcomponent may include a first plurality of polymer particles having BPOdistributed on at least a portion of the surface of the first pluralityof polymer particles and a second plurality of polymer particles havingBPO substantially integrated into or intermixed in at least a portion ofthe second plurality of polymer particles.

In another embodiment of bone cement, the BPO configuration in thenon-liquid component can include polymer particles 716 withmicroencapsulated BPO 712 (see FIG. 19) that is substantially integratedinto the polymer particles 716. These polymer particles 716 may befurther combined with particles 706 of BPO. The BPO particles 706 maypossess a mean diameter ranging between about 1 to 40 μm and may bepresent within the non-liquid component in a concentration rangingbetween about 0.3 to 2 wt. % on the basis of the total weight of thenon-liquid component. In certain embodiments, about 10 to 90% of thetotal BPO content may be integrated into the polymer particles, with theremaining portion of BPO not integrated into the polymer particles. Inother embodiments, about 10-90% of the total BPO content may not beintegrated into the polymer particles, with the remaining portion of BPOintegrated into the polymer particles.

In other embodiments, the BPO configuration in the non-liquid componentmay include particles of BPO integrated into polymer particles andparticles of BPO that are not integrated into polymer particles (e.g.,BPO particles 706). For example, in certain embodiments, about 10 to 90%of the total BPO content may be integrated into the polymer particles,with the remaining portion of BPO not integrated into the polymerparticles. In other embodiments, about 10-90% of the total BPO contentmay not be integrated into the polymer particles, with the remainingportion of BPO integrated into the polymer particles. In anotherembodiment, the BPO configuration in the non-liquid component caninclude a polymer powder or particles 720 with BPO particles 722 milledinto the powder particles, which can cause such BPO particles 722 tosubstantially adhere to a surface of the polymer power particles (seeFIG. 20). Similarly, radiopacifiers can be milled into the surfaces ofthe polymer powder (see FIG. 20). In certain embodiments, the density ofBPO particles 722 and/or radiopacifiers upon the surface of the polymerparticles 720 may range between about 0.01-0.2 g/cm³.

In another embodiment of bone cement, the liquid monomer component caninclude microencapsulated monomer volumes within a sacrificial capsule(not shown).

In further embodiments, the above disclosed bone cement compositions maybe provided in such a manner that the BPO configuration controls theinitiation, or the rate, of chemical reaction caused by mixing theliquid monomer component and the non-liquid component. Thus, in anembodiment of the present disclosure, controlled BPO exposure mayprovide a lengthened setting interval in which the mixture has aflowability property that prevents unwanted extravasation.

In an embodiment, the BPO may be provided in a configuration such thatthe bone cement composition exhibits a viscosity of at least about 500Pa·s within about 30 to 90 seconds after the liquid and non-liquidcomponents are substantially mixed with one another (e.g., post-mixing).In certain embodiments, of the method composition may achieve aviscosity of at least about 500 Pa·s, at least about 1000 Pa·s, at leastabout 1500 Pa·s and at least about 2000 Pa·s within about 30 secondspost-mixing. In other embodiments of the method, the composition mayachieve a viscosity of at least about 500 Pa·s, at least about 1000Pa·s, at least about 1500 Pa·s, at least about 2000 Pa·s and at leastabout 2500 Pa·s within about 60 seconds post-mixing. In furtherembodiments of the method, the composition may achieve a viscosity of atleast about 500 Pa·s, at least about 1000 Pa·s, at least about 1500Pa·s, at least about 2000 Pa·s and at least about 3000 Pa·s within about90 seconds post-mixing.

In further embodiments, the BPO configurations within bone cementcompositions discussed herein may enable the BPO that is exposed to theliquid component of the bone cement composition to be approximatelyconstant over a selected time interval. In certain embodiments, thistime interval may range between about 2 to 10 minutes. In furtherembodiments, the viscosity of the bone cement composition during thistime interval may be greater than about 1000 Pa·s, greater than about1500 Pa·s, greater than about 2000 Pa·s, greater than about 2500 Pa·s,greater than about 3000 Pa·s, greater than about 3500 Pa·s, and greaterthan about 4000 Pa·s.

In another embodiment, the BPO configuration within bone cementcompositions discussed herein may control the amount of BPO that isexposed to the liquid component of the bone cement composition such thatthe composition exhibits a viscosity of less than about 4000 Pa·s afterabout 20 minutes post-mixing, after about 18 minutes post-mixing, afterabout 16 minutes post-mixing, after about 14 minutes post-mixing, andafter about 12 minutes post-mixing. In another embodiment, thecomposition may achieve a viscosity of less than about 3000 Pa·s afterabout 20 minutes post-mixing, after about 18 minutes post-mixing, afterabout 16 minutes post-mixing, after about 14 minutes post-mixing, andafter about 12 minutes post-mixing. In another embodiment, thecomposition may achieve a viscosity of less than about 2000 Pa·s afterabout 20 minutes post-mixing, after about 18 minutes post-mixing, afterabout 16 minutes post-mixing, after about 14 minutes post-mixing, andafter about 12 minutes post-mixing.

In an embodiment, bone cements having such properties may include amonomer component and polymer component such as those described above.In other embodiments, the bone cements may include a monomer componentand a polymer component, where the polymer component includes a firstvolume of beads having a first average wt. % of benzoyl peroxide (BPO),on the basis of the total weight of the first volume of beads, and asecond volume of beads having a second average wt. % of BPO, on thebasis of the total weight of the second volume of beads. In this bonecement embodiment, the first volume of beads may have an average crosssection of less than about 100 microns, less than about 80 microns, lessthan about 60 microns, or less than about 40 microns. The second volumeof beads may have an average cross section of greater than about 40microns, greater than about 60 microns, greater than about 80 microns,and greater than about 100 microns. In a bone cement embodiment, thefirst volume may have less than about 0.5 wt. % of BPO and the secondvolume may have greater than about 0.5 wt. % of BPO. In another bonecement embodiment, the combined first and second volumes may alsoinclude less than about 5.0 wt. % of BPO or less than about 2.5 wt. % ofBPO on the basis of the total weight of the polymer component. In afurther bone cement embodiment, the combined first and second volumeshave greater than about 0.5 wt. % of BPO or greater than about 1.0 wt. %of BPO. In an additional embodiment, at least a portion of the firstvolume is without BPO or at least a portion of the second volume iswithout BPO.

In another embodiment of the present disclosure, the bone cementincludes a monomer component and polymer component, where the polymercomponent includes beads carrying from about 0.2% and 0.6% of BPO, onthe basis of the total weight of the beads. In certain embodiments, atleast about 80% of the BPO is carried on a first portion of beads havinga mean cross section of greater than about 100 microns, and less thanabout 20% of the BPO is carried on a second volume of beads having amean cross section of less than about 100 microns.

In another embodiment of the present disclosure, the bone cementincludes a monomer component and polymer component, where the polymercomponent includes beads carrying from about 0.2% and 0.6% of BPO, onthe basis of the total weight of the beads. In certain embodiments,about 100% of the BPO is carried on a first portion of the beads havinga mean cross section of greater than about 100 microns, andapproximately no BPO is carried on a second portion beads volume havinga mean cross section less than 100 microns.

In another embodiment of the present disclosure, the bone cementincludes a monomer component and polymer component, where the polymercomponent includes beads of at least one polymeric material. The polymercomponent may include from about 0.2% and 3.0% BPO on the basis of thetotal weight of the beads. In further embodiments, a first portion ofthe beads may carry BPO in a surface coating and a second portion of thebeads may carry BPO integrated into the at least one polymeric material.

In another embodiment of the present disclosure, the bone cement mayinclude a monomer component and polymer component, where the polymercomponent includes beads of at least one polymeric material and fromabout 0.2% and 3.0% BPO on the basis of the total weight of the beads.In certain embodiments, the BPO may be provided in at least two of thefollowing forms: as a surface coating on beads, as BPO particles, as BPOin microcapsules, as BPO particles within beads of a polymeric material,and as BPO in microcapsules within beads of a polymeric material.

In one embodiment, depicted in FIG. 21, the concentration or volume ofBPO available may be characterized in a BPO volume (or BPO surface area)versus time plot. For example, in one embodiment of the bone cementcomposition, the slope of the BPO availability curve 750 over time maybe positive in region 755A, and thereafter the slope may beapproximately zero or substantially flat (region 755B) over at least 4minutes, 6 minutes or 8 minutes. In certain embodiments, the BPOavailability within the positive region 755A may initially be zero andthen reach between about 0.004 g/ml/min to 0.04 g/ml/min. Thereafter,the BPO availability may be substantially constant in the above range.In certain embodiments, the total time over which the BPO availabilityvs. time plot exhibits a slope that is approximately zero in apost-mixing interval can be at least 2 minutes, 4 minutes, 6 minutes, 8minutes and 10 minutes. In another embodiment, BPO availability curvecan be controlled in slope over the post-mixing period to flatten,increase in slope or decrease in slope in either direction bycontrolling the amount of BPO exposed to the monomer.

The BPO availability curve in FIG. 21 can be achieved, in certainembodiments, by integrating BPO into polymer particles as depicted inFIG. 16. Upon mixing liquid monomer with the particles 700 and 705, themonomer would rapidly dissolve the small particles 700 which wouldrapidly increase BPO availability resulting in the slope within region755A, and after the small particles 700 were dissolved, then that largerparticles 705 would dissolve slowly exposing a substantially constantamount of BPO to be wetted by the monomer in region 755B of the curve.

In another embodiment of a method of the present disclosure, a method ofmaking a bone cement composition is provided. The method includesproviding a liquid monomer component and polymer component, the polymercomponent having polymer particles contained therein. The method furtherincludes distributing BPO within the polymer particles so as to providea selected BPO availability (e.g., controlled exposure) to the liquidmonomer component over at least first and second time intervals. Incertain embodiments, the BPO may be selectively exposed to the liquidmonomer over the at least first and second time intervals. In certainembodiments, the BPO availability per second over the first timeinterval is substantially greater than the BPO availability per secondover the second time interval. In an embodiment, the first time intervalmay be at least about 1 minute, at least about 2 minutes, and at leastabout 3 minutes. The first time interval can be less than about 5minutes. In other embodiments, the second time interval may be at leastabout 5 minutes, at least about 10 minutes, at least about 15 minutes,at least about 20 minutes, at least about 25 minutes, at least about 30minutes, at least about 35 minutes, and at least about 40 minutes.

FIG. 22 illustrates another embodiment of volume or concentration ofexposed BPO as a function of time. FIG. 22 illustrates curve 800indicating BPO availability over time, indicating the amount of BPO thatmay be available for exposure to the monomer. The first interval 805Amay fall within a range of between about 0.004 g/ml/min to 0.04g/ml/min. FIG. 22 illustrates the second interval 805B in which the BPOavailability is less than the first interval until the BPO availabilityis diminished as the bone cement reaches a setting point. As can be seenin FIG. 22, the composition exhibits a discontinuity in the BPOavailability curve, which provides the cement with an extended workingtime. A bone cement and BPO availability characterized by FIG. 22 can beprovided by a cement formulation described above, or with the use of BPOparticles 706 as in FIGS. 17-19, or BPO surface coatings as in FIGS. 18and 20. The method can further include mixing the liquid monomercomponent and the polymer component and injecting the mixture into bone.In FIG. 22, the BPO availability curve 806 of a conventional PMMA bonecement in shown.

The method can further include mixing the liquid monomer component andthe polymer component and injecting the mixture into bone. In oneembodiment, the BPO availability can be high for about one to fiveminutes post-mixing in order to accelerate an increase in viscosity, andthen the BPO availability can be lower for about the next 5 to 40minutes as the cement is further polymerizing.

In another embodiment, referring to FIG. 23, bone cement precursors canbe characterized by a BPO availability curve 810 that provides highavailability in a first interval 815A, as in FIG. 22, for up to aboutfive minutes to create a rubberized cement condition suited fornon-extravasating injection into bone. Thereafter, BPO availability canbe reduced to about zero for a second interval 815B of about 1 to 20minutes thus maintaining the cement substantially in the rubberizedcondition for injection without substantial extravasation. Thereafter,BPO availability can be increased to a high level for a third interval815C of from 30 seconds to 5 minutes to cause rapid setting of thecement.

Such a BPO availability curve and resulting cement may be provided byusing a non-liquid component consisting of particles 405 as depicted inFIG. 24. In FIG. 24, the BPO particles 822 are milled on the surface ofparticles of PMMA material 820, similar to that of FIG. 20. A surfacelayer of PMMA material 824 interior of the BPO particles 822 is withoutany BPO. Further interior of the PMMA layer 820A, fragmented particlesof BPO coated PMMA particles 820A, with BPO indicated at 822′ and PMMAmaterial indicated at 820B.

It can be understood that upon exposure to the liquid component inmixing, the monomer is initially exposed to the milled BPO surface 822,wetting the surface and thus providing the high BPO availabilityindicated by the first interval 815A of FIG. 23. Thereafter, the BPOavailability would drop to zero as indicated in second interval 815B ofFIG. 23. During this interval, the monomer would slowly dissolve thelayer of PMMA material 824. At a selected subsequent point in time,depending on the selected thickness of the PMMA layer 824, the monomerwould reach the BPO layer 822′ and thus BPO availability would increaseas shown in third interval 815C of FIG. 23. The packed togetherparticles 820 can separate and all BPO surface areas of these particlesmay then be exposed to the monomer. A bone cement composition thatresults from mixing liquid and non-liquid components as described abovewould then provide a cement composition having a time-viscosity curve840 as shown in FIG. 25, which is superimposed over the BPO availabilitycurve of FIG. 23.

In certain embodiments of this method, the selected BPO availability isprovided by at least two different particles having differing BPOconfigurations therein. In one embodiment, the selected BPO exposure maybe provided by a controlling BPO exposure to the monomer component on atleast a portion of the surface area of the particles. In anotherembodiment, the selected BPO exposure may be provided, at least in part,by particles comprising a mixture of a polymeric material and BPO. Inanother embodiment, the selected BPO exposure may be provided, at leastin part, by particles having a surface coating of BPO. In anotherembodiment, the selected BPO exposure may be provided, at least in partby, microencapsulated BPO. In another embodiment, the selected BPOexposure may be provided by particles having layers of polymericmaterials and BPO.

In another embodiment of a method of the present disclosure, the mixablebone cement may exhibit a selected interval in which the release orexposure of BPO or other initiator is controlled. In this manner, aselected concentration or volume of free BPO within the composition maybe achieved over a selected time interval. In one embodiment, free BPOincludes the volume of BPO, or other initiator, that is available orexposed to the liquid monomer post-mixing.

In one specific formulation of a PMMA bone cement, the solid or powdercomponent of the bone cement may include: PMMA, BPO, and ZrO₂. In oneembodiment, polymethylmethacrylate polymer (PMMA) is present within thebone cement in a concentration ranging between about 45%-55 wt. % on thebasis of the total weight of the powder component. In other embodiments,the concentration of PMMA is about 49.6 wt. %. In other embodiments, theBenzoyl Peroxide (BPO) is present in a concentration ranging betweenabout 0.30-0.80% on the basis of the total weight of the powdercomponent In other embodiments, the concentration of BPO is about 0.40wt. %. In additional embodiments, the concentration of Zirconium Dioxideor Barium Sulfate may range between about 45%-55% on the basis of thetotal weight of the powder component. In another embodiment, theconcentration of Zirconium Dioxide or Barium Sulfate is less than orequal to about 50.0 wt. %.

In this cement formulation, the liquid component of the bone cementincludes Methylmethacrylate (MMA), N, N-dimethyl-p-toluidine (DMPT), andHydroquinone (HQ). In one embodiment, the concentration ofMethylmethacrylate (MMA) may range between about 98.0-99.9 wt. % on thebasis of the total weight of the liquid component. In other embodiments,the concentration of MMA may be about 99.5%. In other embodiments, theconcentration of DMPT may range between about 0.15-0.95 wt. % on thebasis of the total weight of the liquid component. In other embodiments,the concentration of DMPT may be about 0.50%. In other embodiments, theconcentration of HQ may range between about 30-150 ppm on the basis ofthe total amount of the liquid component. In other embodiments, theconcentration of HQ may be about 75 ppm.

In embodiments of this cement formulation, the powder PMMA component asdescribed above may include a blend of a plurality of PMMA powdersdistinguished by one or more of PMMA molecular weights, particle sizes,and/or concentrations of BPO contained within the powder.

For example, in one embodiment of the bone cement composition, three (3)PMMA powders, Powders 1, 2 and 3, may be provided. The ratio of amountsof each of powders 1, 2, and 3 may range between about 40 to 50% forpowder 1, 30 to 40% for powder 2, and the remainder comprising powder 3.In one embodiment, powders 1, 2, and 3 are mixed in a ratio of: Powder1=44.28%; Powder 2=36.86% and Powder 3=18.86%.

Powder 1 may include a target particle size having a range of about100-120 μm, for example, about 110 microns. The molecular weight of PMMAof powder 1 may range between about 150,000 to 350,000, for example,about 350,000. Powder 1 may further include about 0.9-1.1 wt. % BPO onthe basis of the total weight of the powder component. In certainembodiments, powder 1 may include about 1.0 wt. % BPO.

Powder 2 may include a target particle size having a range of about70-90 μm, for example, about 80 microns. The molecular weight of PMMA ofpowder 2 may range between about 300,000 to 500,000, for example, about400,000. Powder 2 may further include about 1.1 to 1.3 wt. % BPO on thebasis of the total weight of the powder component. In certainembodiments, powder 2 may include about 1.2 wt. % BPO.

Powder 3 may include a target particle size having a range of about 25to 45 μm, for example, about 35 microns. The molecular weight of PMMA ofpowder 3 may range between about 250,000 to 450,000, for example, about250,000. Powder 3 may further include about 0.0-1.1 wt. % BPO on thebasis of the total weight of the powder component. In certainembodiments, powder 3 may include approximately no BPO.

In some conventional vertebroplasty and kyphoplasty procedures, bonecement is injected into a fractured vertebral body to act as an internalcast to stabilize the fractured bone. Stabilization of the fracture caneliminate micromotion, which typically can eliminate pain associatedwith the fracture. A typical bone cement includes a self-curing polymersuch as PMMA that is produced by mixing a first liquid monomer componentand a second non-liquid polymer component. Many commercially availablebone cements use methyl methacrylate as a liquid monomer component andmethylmethacrylate as a principal powder component. After mixing thefirst and second components, the mixture sets or self-cures uponpolymerization and crosslinking of the components.

In RF kyphoplasty, which can use a system with a heating element toapply energy to the bone cement as described above, the bone cement canbe formulated for application of heat from an RF source to cause rapid,controlled polymerization and greater viscosity during injection toinhibit unwanted extravasation. In such an RF kyphoplasty procedure, theapplied energy is complementary to the self-curing chemical reactionthat occurs upon mixing a monomer and polymer.

In an operating environment, bone cement for conventionalvertebroplasty/kyphoplasty procedures and/or RF kyphoplasty is typicallymixed at a back table in an operating room immediately before itsinjection into a patient. There are at least two important, and related,operating parameters relating to the preparation and use of aself-curing bone cement, which are indicated in FIG. 26. A firstoperating parameter is the “start time” or “start delivery time” whichis a predetermined number of minutes post-mixing generally characterizedby a certain degree of polymerization of the cement mixture which allowsfor flowability as well as a desired viscosity. The “post-mixing” timerefers to minutes post or after the “initiation of mixing time” (seeFIG. 26) of the bone cement components. A second important operatingparameter is total “working time” of the cement, which is the timeinterval between the start delivery time and a stop delivery time—thepoint in time that the cement is too viscous to be injected. Whether thebone cement is too viscous can depend on many factors, such as thedelivery pressures and the desired delivery viscosity. In someembodiments, it can be desirable to deliver bone cement at about3,000-6,000 Pa*s, or at about 5,000-9,000 Pa*s. In some embodiments, thebone cement can be too viscous at about or greater than: 10,000, 12,000,or 15,000 Pa*s. Another operating parameter is the cement viscosityitself—which preferably is a predictable minimum level that can bedetermined by the interval of minutes post-mixing and thus is directlyrelated to the start-time. The viscosity parameter can be important forpreventing extravasation and also for determining injection pressurerequirements over the interval of the cement working time. Another timepoint beyond the end of the working time interval is the set time, atwhich time the cement is cured or substantially cured. The set time thusalso can be calculated relative to the initiation of mixing time.

The polymerization and curing of bone cements can be retarded by cooltemperatures in an operating environment or accelerated by warmtemperatures in an operating room, thus affecting the start deliverytime and cement working time. Likewise, if the cement precursors(monomer and polymer) are stored in a cooler or warmer temperaturerelative to the operating environment, the variance in temperatures canalso affect the cement operating parameters.

Referring back to FIG. 14, as was discussed previously, this chart showsthe change in viscosity over time of a bone cement when heated todifferent temperatures. A similar chart could be made showing thedifferences in viscosity over time with different starting temperatures.In general, as in FIG. 14, the higher the start temperature the fasterthe viscosity increase over time. In one embodiment, a controller (e.g.,electronic or computer controller) such as the controller 145 cancontrol the operation of the system 10 for delivering bone cement basedat least in part on an algorithm that models the different rate ofviscosity increase of a bone cement at different starting temperatures.

For example, in one embodiment, assuming a default or set desireddelivery viscosity, a physician or nurse with a starting temperature ofthe bone cement precursors can then determine the bone cement deliverystart time with the use of a chart or a computer program or controller(e.g., electronic or computer controller), such as the controller 145.In some embodiments, the user can start with both the startingtemperature and the desired viscosity and determine the bone cementdelivery start time.

In another aspect, a method of using a curable bone cement in a surgicalprocedure can be provided which can include the steps of (1) acquiringtemperature data of at least one bone cement precursor prior to mixingthe at least two bone cement precursors; and (2) acquiring and/orgenerating a signal of an operating parameter of the cement to therebyallow a controller and/or physician to alter a procedural step. Morespecifically, one preferred operating parameter is a temperature of abone cement precursor.

In another aspect relating to components of FIGS. 6, 27 and 28, a kitthat includes bone cement pre-cursors such as a liquid monomer componentand/or a non-liquid polymer component, can further include a temperaturesensor carried on the surface of a container of either or bothprecursors, or on a surface of the packaging or mixing assembly. Thetemperature of the component or components can then be taken intoconsideration to determine the start-time for using the mixed cement. Ingeneral, a kit for providing a self-curing bone cement can include afirst container containing a first component of the bone cement, and asecond container containing a second component of the bone cement,wherein at least one container has a surface carrying a sensor 274. Thesensor 274 can be one of many different types of sensors including atemperature sensor.

FIG. 27 shows a temperature sensor 274 affixed to a monomer vial 271.FIG. 28 shows a temperature sensor 274 affixed to packaging 273 of amonomer vial 271. In some embodiments, the temperature sensor 274 can bea temperature strip 278. The temperature strip can be a thermostripdevice available from LCR Hallcrest, also known as Liquid CrystalResources, LLC, 1820 Pickwick Lane, Glenview, Ill. 60026. In oneembodiment, the temperature strip 278 can include micro-encapsulatedliquid crystal compounds that carry an ink or dye that change colorbased on temperature. Such liquid crystals include chemical compoundsthat exhibit the mechanical properties of liquids and the opticalcharacteristics of solids, and are known as thermochromic liquidcrystals (TLC's), or as cholesteric liquid crystals.

In some embodiments, one or more of the bone cement precursors cancontrol the temperature or greatly influence the temperature of the bonecement. For example, in some embodiments, a liquid monomer can changetemperature at a slower rate than a powder component. In someembodiments, the start temperature can be the temperature of a bonecement precursor or the temperature history of the bone cementprecursor. In some embodiments, a temperature sensor, such as thetemperature sensor 274, can be on or in the packaging and/or containerof only one of the bone cement precursors, such as the precursor whosestarting temperature has the greatest influence on the rate of viscositychange of the bone cement.

In some embodiments, the packaging and/or container holding a liquidmonomer component can include a temperature sensor, such as atemperature strip (e.g., the temperature strip 278). Where, for example,a cold monomer component can warm slowly and the temperature of a PMMApowder can very quickly adjust to ambient room temperature, thetemperature of the liquid monomer can be used to determine the rate ofchange of the viscosity over time of the bone cement after the bonecement components are mixed together.

In some embodiments a method can include the step of placing one or moreof the bone cement precursors in the ambient atmosphere of a treatmentroom for a desired period of time prior to mixing. In some embodiments,said desired period of time prior to mixing can include at least about:30, 45, and 60 minutes prior to mixing. In some embodiments, a starttemperature can include the ambient room temperature, especially whereone or more of the bone cement precursors are exposed to the ambienttemperature of a treatment room prior to mixing.

In some embodiments, a kit carries at least one temperature sensor 274that can include a visual display, that can further include athermochromic ink or thermochromic liquid crystals.

In other embodiments, a kit carries at least one temperature sensor thatincludes a wireless transmitter (e.g., RF transmitter) component fortransmitting the temperature data to another device (e.g., to a computercontroller) in a wireless manner.

In other embodiments, a kit includes a wireless device 277 (e.g., RFtransmitter, RF tag) for conveying information data to another device279 (e.g., to a computer controller) in a wireless manner. The wirelessdevice 277 can convey information on its own or in response to a signalfrom another device 279. The data can include data about the product,such as, whether the product is a liquid monomer or a powder component,or sensor data, such as, temperature or temperature history. Thewireless transmitter 277 can be a stand alone device or can be part ofthe sensor 274. The other device, such as a computer controller, canprovide the conveyed information, and/or additional information to otherdevices and/or operators.

In one embodiment, the container 271 carrying the sensor can be a vialcontaining a liquid monomer or a body containing a powder. The body canbe a vial, ampule, tube, syringe, bag or sac. Alternatively, the sensorcan be affixed to packaging 273, which can include at least one of ashipping carton, box, bag, tube, sterile pouch, sterile sac and blisterpack. The sensor 274 can be on an interior or exterior surface.

In some embodiments, a system for providing a bone cement for injectioninto a patient, can include a first package containing a liquid monomerand a second package containing a polymer powder; a data transmitter(e.g., a radio frequency tag/temperature sensor) carried by at least onepackage to provide output data; and a data receiver for receiving theoutput data and providing a signal to a controller and/or systemoperator. The output data can include an ID parameter selected from thegroup of monomer or polymer type, volume of monomer or polymer, andmanufacturing lot of the monomer of polymer. Further, the output datacan include a temperature of the monomer or polymer, or a temperaturelog or history of the monomer or polymer. The system can be configuredto provide signals that are at least one of electronic data or anaudible, visual or tactile signal.

In some embodiments, a system can provide a signal that indicates apost-mixing start time for injecting the cement. In some embodiments,the signal can indicate a stop time for injecting the cement, cementviscosity, or cement temperature.

A method for providing operational information concerning a bone cementcan include (1) providing one or more bone cement precursors of bonecement in a kit with a temperature sensor affixed thereto; (2) mixingthe bone cement precursors to provide a bone cement; and (3) determiningthe bone cement injection start time based on temperature of one or moreof the bone cement precursors. The method can have a determining stepthat is derived from a chart, or the determining step can be provided byan algorithm and computer controller.

Another method for providing operational information concerning a bonecement can include (1) providing one or more bone cement precursors ofbone cement in a kit with a radio frequency tag affixed thereto; (2)transmitting an interrogation signal to the radio frequency tag from acontroller; (3) receiving a response signal from the radio frequency tagindicating data concerning one or more bone cement precursors; and (4)determining an operational step based on the data. The data can includetemperature and/or temperature history. The operational step can be thecement delivery start time or the cement delivery stop time.

Another method can determine a working condition of a curable bonecement, wherein the steps of the method can include (1) determining thepre-mix temperature of at least one of first and second bone cementprecursors; (2) determining the ambient temperature; (3) mixing thefirst and second bone cement precursors; and (4) utilizing an algorithmrelating to pre-mix and ambient temperatures to thereby determine acement injection start time. The method can further include actuating acontroller and energy source to apply energy through an emitter tothereby apply heat to the bone cement post-mixing. The method canfurther include actuating the controller to modulate applied energybased on the pre-mix and ambient temperatures and/or the calculatedinjection start time. The method can further include actuating thecontroller to modulate hydraulic pressure based on the pre-mix andambient temperatures and/or the calculated injection start time.

In the above methods, the determining steps can be accomplished at leastby one temperature sensor affixed to containers and/or packaging of thefirst and second bone cement precursors.

Another aspect can provide a method of determining a working conditionof a curable bone cement which can include (1) determining the pre-mixtemperature history of at least one of the first and second bone cementprecursors; (2) determining the ambient temperature; (3) mixing thefirst and second bone cement precursors; and (4) utilizing an algorithmrelating to pre-mix and ambient temperatures to thereby determine acement injection start time.

A method of using a curable bone cement in a surgical procedure caninclude (1) acquiring temperature data of at least one bone cementprecursor prior to mixing at least two bone cement precursors; and (2)generating a signal of an operating parameter of the cement to therebyallow a controller and/or physician to alter a procedural step.

Specific characteristics and features of the systems and methods aredescribed in relation to some figures and not in others, and this is forconvenience only. While the principles of the invention have been madeclear in the exemplary descriptions and combinations, it will be obviousto those skilled in the art that modifications may be utilized in thepractice of the invention, and otherwise, which are particularly adaptedto specific environments and operative requirements without departingfrom the principles of the invention. Consequently, the scope of thepresent teachings should not be limited to the foregoing discussion, butshould be defined by the appended claims.

Of course, the foregoing description is that of certain features,aspects and advantages of the present invention, to which variouschanges and modifications can be made without departing from the spiritand scope of the present invention. Moreover, the bone treatment systemsand methods need not feature all of the objects, advantages, featuresand aspects discussed above. Thus, for example, those of skill in theart will recognize that the invention can be embodied or carried out ina manner that achieves or optimizes one advantage or a group ofadvantages as taught herein without necessarily achieving other objectsor advantages as may be taught or suggested herein. In addition, while anumber of variations of the invention have been shown and described indetail, other modifications and methods of use, which are within thescope of this invention, will be readily apparent to those of skill inthe art based upon this disclosure. It is contemplated that variouscombinations or subcombinations of these specific features and aspectsof embodiments may be made and still fall within the scope of theinvention. Accordingly, it should be understood that various featuresand aspects of the disclosed embodiments can be combined with orsubstituted for one another in order to form varying modes of thediscussed bone treatment systems and methods.

What is claimed is:
 1. A bone cement kit package, comprising: a firstcontainer containing a liquid component comprising a monomer; a secondcontainer containing a non-liquid component comprising at least twopolymer bead populations having different average sizes and differentweight percentages of a radical initiator, wherein the liquid componentand the non-liquid component are configured to, upon mixing, form amixture that cures at least in part by self-heating by undergoing anexothermic reaction; and a temperature sensor affixed to an outersurface of a packaging material of the bone cement kit package and usedto indicate a pre-mix temperature of at least one of the non-liquidcomponent and the liquid component inside the bone cement kit packageprior to mixing the non-liquid component and the liquid componenttogether.
 2. The bone cement kit package of claim 1, wherein one of thepolymer bead populations having a smaller average size than another oneof the polymer bead populations has a higher weight percentage of theinitiator than the another one of the polymer bead populations.
 3. Thebone cement kit package of claim 1, wherein the liquid componentcomprises an activator at a concentration less than about 1% based on anoverall weight of the liquid component.
 4. The bone cement kit packageof claim 3, wherein the initiator comprises benzoyl peroxide (BPO) andthe activator comprises N,N-dimethyl-p-toluidine (DMPT).
 5. The bonecement kit package of claim 1, wherein the liquid component and thenon-liquid component are configured to, upon mixing, self-heat themixture to a peak temperature not exceeding 75 degrees.
 6. The bonecement kit package of claim 1, wherein the pre-mix temperature has beenpredetermined to have an associated post-mixing setting time.
 7. Thebone cement kit package of claim 6, wherein the associated post-mixingsetting time is greater than 25 minutes.
 8. A bone cement kit package,comprising: a first container containing a liquid component comprising amonomer; a second container containing a non-liquid component comprisingat least two polymer bead populations having different average sizes anddifferent weight percentages of a radical initiator, wherein the liquidcomponent and the non-liquid component are configured to, upon mixing,form a mixture that cures at least in part by self-heating by undergoingan exothermic reaction; and a temperature sensor affixed to an outersurface of one of the first and second containers having a componentwhose pre-mix temperature changes at a slower rate compared to the otherone of the first and second containers having another component, whereinthe temperature sensor is used to indicate a pre-mix temperature of atleast one of the non-liquid component and the liquid component insidethe bone cement kit package prior to mixing the non-liquid component andthe liquid component together.
 9. The bone cement kit package of claim8, wherein one of the polymer bead populations having a smaller averagesize than another one of the polymer bead populations has a higherweight percentage of the initiator than the another one of the polymerbead populations.
 10. The bone cement kit package of claim 8, whereinthe liquid component comprises an activator at a concentration less thanabout 1% based on an overall weight of the liquid component.
 11. Thebone cement kit package of claim 10, wherein the initiator comprisesbenzoyl peroxide (BPO) and the activator comprisesN,N-dimethyl-p-toluidine (DMPT).
 12. The bone cement kit package ofclaim 8, wherein the liquid component and the non-liquid component areconfigured to, upon mixing, self-heat the mixture to a peak temperaturenot exceeding 75 degrees.
 13. The bone cement kit package of claim 8,wherein the pre-mix temperature has been predetermined to have anassociated post-mixing setting time.
 14. The bone cement kit package ofclaim 13, wherein the associated post-mixing setting time is greaterthan 25 minutes.
 15. The bone cement kit package of claim 8, wherein thesensor is affixed to the first container containing the liquidcomponent.